Download Homologous pigmentation mutations in human, mouse and other

 1997 Oxford University Press
Human Molecular Genetics, 1997, Vol. 6, No. 10 Review
1613–1624
Homologous pigmentation mutations in human,
mouse and other model organisms
Ian J. Jackson
MRC Human Genetics Unit, Western General Hospital, Crewe Road, Edinburgh EH4 2XU, UK
Received May 13, 1997
Mouse coat colour genes have long been studied as a paradigm for genetic interactions in development. A
number of these genes have been cloned and most correspond to human genetic disease loci. The proteins
encoded by these genes include transcription factors, receptor tyrosine kinases and growth factors, G-protein
coupled receptors and their ligands, membrane proteins, structural proteins and enzymes. Many of the mutations
have pleiotropic effects, indicating that these proteins play a wider role in developmental or cellular processes.
In this review I tabulate the available data on all pigmentation genes cloned from mouse or human, and I focus
on three particular systems. One family of genes, including LYST and HPS/ep, shows the relationship between
melanosomes and lysosomes. The G-protein coupled receptor, endothelin receptor-B, and its ligand,
endothelin-3, are required for the development of both melanocytes and enteric neurons. The melanocortin-1
receptor is expressed only on melanocytes, but mutations that cause overexpression of agouti protein, an
antagonist of the receptor, result in obesity, and highlight a role of melanocortins in weight homoeostasis.
INTRODUCTION
Mouse coat colour genes were among the first mammalian mutant
genes known. For most of this century they have been studied as
a model of the way genes interact to regulate the developmental
and cellular function of the pigment cell or melanocyte. There are
about 80 classical mutations that have an effect on mouse coat
colour. To date, 17 of the genes underlying these mutations have
been cloned, and in 14 cases there is a human mutant phenotype
described for the corresponding human gene. There are good
molecular data too that at least six have mutations in other
mammalian species. In contrast there is only a single human
genetic pigmentation disease locus that does not correspond to a
known mouse mutation. This information is summarised in Table
1 which also provides references for all the loci. Much of the
molecular information has also been summarised in recent
reviews (1,2). In this article I will concentrate on the molecular
genetics of three systems in which there has been significant
recent progress in mouse, human and other mammals. Each of
these systems highlights the fact that developmental and cellular
processes that characterise melanocytes may also be found in
other cell types. Mutations affecting melanocytes, which are
readily found because of their effect on pigmentation, will quite
often be found to affect other processes. (Nomenclature note: in
this review, gene symbols are italicised, their protein products are
non-italic. Human gene and protein symbols are all capitalised.
Where a mouse gene product is known, the gene and protein
symbols are lower case with an initial capital.)
I will first summarise work on two genes that encode proteins
involved in the structure and/or function of both melanosomes
and lysosomes and which are members of a larger family of
functionally related genes. Secondly, two G-protein coupled
receptors have been identified that are necessary for normal
melanocyte development and function. These are the endothelin
receptor B (Ednrb/EDNR3) and the melanocortin 1 receptor
(Mc1r/MC1R). Coat colour mutations in mouse Ednrb and its
ligand endothelin 3 (Edn3) have been known for many years, but
their molecular identity only became known recently. Similarly,
mutations in a pair of genes that had opposing effects on the type
of pigment made by hair follicle melanocytes had been studied for
a long time before their identity was established as the
melanocortin 1 receptor and a functional antagonist of this
receptor, the agouti protein. Throughout pigmentation genetics
the similarities and differences between phenotypes of mutations
of the same gene in different species have proved very
informative for deducing how the gene products function in
normal development and physiology.
MELANOSOMES AND LYSOSOMES
The site of melanin synthesis within melanocytes is an organelle
called the melanosome. This becomes filled with melanin before
it is transferred from the cell to neighbouring keratinocytes. A
large body of evidence suggests a close relationship between
melanosomes and lysosomes. Several proteins, such as
lysosomal-associated membrane protein-1 (LAMP-1), and at
least five lysosomal hydrolases are found in fractionated
melanosomes (3,4). Furthermore, if the melanogenic enzymes,
tyrosinase and TRP-1, which normally localise to the
melanosome, are expressed in non-melanogenic cells, they are
found in lysosomes (5). Genetic evidence in support of this
relationship comes from a series of a dozen mouse loci, mutations
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1614 Human Molecular Genetics, 1997, Vol. 6, No. 10 Review
of which have an effect on pigmentation because of abnormal
melanosomes but also affect the secretion of kidney lysosomal
enzymes and have defective platelet dense granules. This last
defect gives rise to a deficiency of the platelet storage pool, and
hence a prolonged bleeding time (6–9). At least two human
disorders, Chediak–Higashi syndrome (CHS) and Hermansky–
Pudlack syndrome (HPS), have a similar range of disorders and
have now been shown to be homologous to two of the mouse
mutations, beige (bg) and pale ear (ep). Griscelli disease is a
disorder similar to CHS, affecting pigmentation and immune
function. The gene has recently been shown to encode Myosin-V,
which is mutated in the dilute mouse mutation (10).
CHS and beige
Although the storage platelet deficiency family of mutations have
many similarities, there are also differences between them. It had
long been suspected on the basis of similarity of phenotype that
the mouse beige mutation and human CHS (OMIM 214500) are
homologous. Additional evidence came from the demonstration
that the lysosomal trafficking defect seen in fibroblasts from
mutant mice and humans did not complement following cell
fusion (11). Fibroblasts from a strain of mink, known as Aleutian,
also failed to complement the CHS or beige defect, indicating that
this too is a homologous mutation. Initial mouse crosses mapped
beige close to a marker, Nid, on chromosome 13 (12). This
segment of the mouse genome is homologous to the telomeric end
of human chromosome 1q, and CHS was mapped to this region
by linkage in families and by homozygosity in individuals from
consanguinous families (13,14).
The complementation assay in somatic cells was a key to
isolating the mouse beige gene. Perou et al. (15) were able to use
YACs containing Nid to complement the lysosomal defect in
beige fibroblasts, and subsequently were able to isolate from the
YAC 6.5 kb of cDNA from a gene within 100 kb of Nid which was
mutated in certain beige alleles (Table 2). A second group
produced a high resolution genetic map and a YAC contig around
beige which they used to select cDNAs including ∼5 kb of
sequence that was mutated in certain other beige alleles (16)
(Table 2). Surprisingly, the two cDNAs did not overlap, but once
the full length, 12 kb, cDNA from humans was isolated it became
clear that the two cDNAs were from the 3′ and 5′ ends,
respectively of the same mRNA (17,18). This mRNA encodes a
large protein named LYST (lysosomal trafficking regulator) that
consists of 3801 amino acids. Analysis of CHS patients has
identified eight mutations to date in this gene (16–19) (Table 2),
which all produce truncated products.
Table 1. Summary of all cloned pigmentation mutations of mouse and human
Class of encoded
protein
Gene
product
Mouse classical
mutation
Human disease
mutation
Transcription factor
PAX3
splotch
Waardenburg syndrome 1
Other
species
Ref.
24–26
Waardenburg syndrome 3
Receptor tyrosine
kinase and ligand
G-protein coupled
MITF
microphthalmia
Waardenburg syndrome 2
KIT
dominant white spotting (W)
Piebaldism
Mast cell factor (Kit-ligand)
steel
none described
Endothelin receptor B
piebald
Hirschsprung disease,
Endothelin 3
lethal spotting
receptor and ligands
24,76,77
pig
78–82
rat
see Table 4
83–85
Shah–Waardenburg disease
Hirschsprung disease
see Table 5
Shah–Waardenburg
CCHS
Melanosome and
Melanocortin 1-receptor
extension, sombre,
associated with skin type I,
horse, cattle, chicken,
(MC1R)
recessive yellow
and/or red hair
guinea-pig, fox
Agouti protein
non-agouti;
none described
fox
(MC1R antagonist)
dominant yellow
mink
see Fig. 1
57,65,67,68,86
LYST
beige
Chediak–Higashi syndrome
HPS/Hps
pale ear
Hermansky–Pudlak syndrome
Melanosome distribution
Myosin V
dilute
Griscelli disease
yeast?
10,87,88,
Copper transport
ATP7A
mottled
Menkes disease
yeast?
89–93
Melanogenic enzymes
Tyrosinase
albino
1,2,94–97
lysosome function
see Table 2
see Table 3
occipital horn syndrome
Other membrane proteins
Oculocutaneous albinism I
rabbit
Ocular albinism
Medaka fish
rat
Tyrosinase Related Protein-1
brown
OCA-III
Dopachrome tautomerase
slaty
none described
1,98–101
102,103
no function ascribed,
pink-eyed dilution
OCA-II
2,97,104–108
silver
none descibed
109,110
none
ocular albinism I
111–114
possible transport function
Melanosomal matrix protein,
possibly enzyme
no function ascribed
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Table 2. Mutations of the LYST (CHS/beige) gene
Species
Mutation
Molecular defect
mouse
bg
partial LINE1 insertion: abnormal splicing, frameshift, protein truncation
15
bg 8J
CGA→TGA, nonsense mutation, protein truncation
15
bg 11J
5 kb deletion: predicts incorrect splice, protein truncation
16
bg 2J
>5× decrease in mRNA: molecular nature not defined
16
childhood CHS
homozygous 1 bp deletion, codon 489, frameshift, protein truncation
17
childhood CHS
homozygous 1 bp insertion, codon 633/634, frameshift, protein truncation
18
childhood CHS
homozygous 1 bp deletion, codon 3197, frameshift, protein truncation
18
childhood CHS
homozygous CGA→TGA, nonsense mutation, codon 1029
19
childhood CHS
compound heterozygote; 2 bp deletion, codon 1026, frameshift, protein truncation
19
human
Ref.
Second mutation not detected
childhood CHS
compound heterozygote, 1 bp insertion codon 40, frameshift, protein truncation
16, 17, 19
Second allele transcriptionally silent
mild CHS
compound heterozygote: CGA→TGA, nonsense mutation, codon 50, second
19
mutation not detected
late onset CHS
homozygous CGA→TGA, nonsense mutation, codon 1103, protein truncation
The sequence of the full length LYST protein has interesting
features but does not provide any definitive answers as to its
function. A 350 amino acid region near to the C-terminus has
significant similarities to a number of proteins, including part of
another human protein with some similarity to the cell cycle
control protein CDC4, but of unknown function, a yeast ORF of
unknown function, and three different Caenorhabditis elegans
anonymous ORFs. A short 72 amino acid segment of the protein
near the N-terminus has limited similarity (26%) to stathmin,
which is a protein that regulates microtubule polymerisation. Nagle
et al. (17) describe the presence of 23 hydrophobic helices
throughout the length of the protein. These are analogous to (but
do not have sequence similarity with) repeated motifs called HEAT
and ARM which are seen in other proteins. Several proteins with
these motifs are involved in vesicle transport, as LYST appears to
be. The N-terminal part of Lyst also contains seven repeats of a
motif known as WD40, which is thought to be involved in
protein/protein interaction. A yeast protein, the product of the
VPS15 gene, also has both HEAT/ARM motifs and N-terminal
WD40 repeats. VPS15 is one of a large number of genes that are
involved in directing proteins vacuole; the yeast lysosome.
However, VPS15 is a serine/threonine kinase and is part of a signal
transduction mechanism, and there is no evidence for such a
function of Lyst.
HPS and pale ear
HPS (OMIM 203300) is a second human disorder that combines
oculocutaneous albinism with a lysosomal storage defect and a
bleeding disturbance. Although generally rare, two genetically
fairly isolated populations have been noted where it is common;
presumably due to a founder effect. Using these populations, from
Puerto Rico and from the Swiss Alps, the HPS gene could be
mapped to a fairly narrow interval of chromosome 10 (20).
Isolation of a YAC and BAC/PAC contig across the region gave
rise to more markers that refined the interval to <200 kb using the
Puerto Rican patients (21). Two genes were identified in this
interval, one of which was mutated in HPS patients. All Puerto
Rican patients are homozygous for a 16 bp duplication that results
17
in a frameshift and truncation of the protein (Table 3). All the
Swiss individuals are homozygous for a different mutation, due
to a single base insertion. This insertion, of an additional C in a
run of eight, might be a recurrent mutation as it has been seen in
an unrelated Irish patient within a different haplotype. A third
mutation has been characterised in a Japanese individual (21)
(Table 3).
The location of HPS on chromosome 10 permits the
identification, by conserved linkage, of the precise region of the
mouse genome on chromosome 19 where the mouse HPS
homologue must lie. Two closely linked mutations are candidates,
ruby eye (ru) and pale ear (ep). Sequencing of the mouse HPS
homologue from ru and ep mice found the gene mutated in ep
DNA and in a second mutant allele ep 6J (22) (Table 3).
The protein encoded by this gene has no obvious features to
indicate its function, except for two potential transmembrane
domains, suggesting that it is localised in the melanosomal or
lysosomal membrane with both termini in the lumen and a
cytoplasmic loop (although it has no signal sequence). It bears no
similarity to any other proteins in the database, with the exception
of a seven or eight amino acid stretch that is identical between
LYST and HPS/ep. As both proteins are probably localised in the
organellar membrane, this may indicate an interaction with a
common protein. However, it is thought that LYST is located on
the cytoplasmic side of the membrane, and the peptide motif in
HPS/ep is on the lumenal side; the interacting protein would have
to span the membrane or be localised on both sides (23).
It is interesting to note that all the mutations characterised to
date in the human HPS or mouse ep gene result in truncations.
Both mouse mutations truncate the protein within 90 amino acids
of the C-terminus and two of the three human mutations retain
two thirds of the protein, including both transmembrane domains.
No differences between the patients have been reported that might
correlate with more or less truncated protein products. The mouse
ep truncation has lost only 46 amino acid residues (although it
also has 92 ‘nonsense’ residues added) and still has a full pale ear
phenotype, indicating that the C-terminus of the protein is
essential for its function.
1616 Human Molecular Genetics, 1997, Vol. 6, No. 10 Review
Table 3. Mutations of the HPS/ep gene
Species
Mutation
Molecular defect
Ref.
mouse
ep
IAP insertion, codon 657, protein truncation
22
ep6J
23 bp deletion, 3 bp insertion, codons 611–618, frameshift, protein truncation
22
human
Puerto Rican families
16 bp duplication, frameshift codon 496, protein truncation
21
Swiss families
single base insertion (duplication), codon 324, frameshift, protein truncation
21
Japanese
single base insertion (duplication), codon 441, frameshift, protein truncation
21
The HPS/ep protein may be less important for melanosomal
function than for lysosomes and platelets. Whilst pale ear mice
have the typical features of lysosome storage diseases and
prolonged bleeding time, their hair pigmentation is not severely
affected in adults, unlike the pale ear and tail. Pigmentation of ears
and tail is produced by melanocytes in the epidermis, whereas
hair is pigmented by follicular melanocytes. The density of
melanocytes is much greater in the skin and possibly a slight
reduction in melanin production is more easily observed in the ear
and tail than in the hair.
ENDOTHELIN 3 AND MELANOBLAST
DEVELOPMENT
Melanocytes and neural crest
Melanocytes originate during development from the neural crest.
These are cells that migrate from either side of the dorsal neural
tube soon after it has formed by folding of the neural plate. Neural
crest gives rise to numerous cell types, including neuronal and
glial cells of the peripheral nervous system, cells of the adrenal
gland and craniofacial structures as well as pigment cells.
Mutations that affect this process, or a common precursor within
the lineages will, of course, affect more than one cell type. The
transcription factor PAX3, for example, is required early in the
process. Individuals heterozygous for PAX3 mutations have
Waardenburg syndrome type 1, and have both abnormal facies
and a melanocyte deficiency (24). Splotch mutant mice have
mutations in Pax3 and similar defects. When splotch is
homozygous it results in lethality due to a severe neural crest
defect (25,26).
An old classical mouse mutation named piebald (s) specifically
affects two neural crest-derived lineages. The mutation is
recessive, and when homozygous results in mice that have a
variable degree of white spotting. Numerous other alleles of the
mutation exist, most of which are more severe. Homozygotes for
these mutations lack virtually all pigmentation of the hair and skin
(but have dark eyes, as the retinal pigmented epithelium is not of
neural crest origin). Furthermore, these animals develop
megacolon due to absence of neural crest-derived enteric ganglia
and consequently often die. Mice mutant at a second locus, lethal
spotting (ls), have a very similar phenotype, with white spots and
megacolon. Both mutations are reminiscent of some forms of
Hirschsprung disease (HSCR) (OMIM 142623), which is
characterised by colonic aganglionosis, and some patients have
unpigmented regions, such as a white forelock, eyebrows and
eyelashes. About half of familial and 15–20% of sporadic HSCR
patients have mutations of the Ret receptor tyrosine kinase (27).
Others have deletions on chromosome 13q, and in an inbred
pedigree a recessive form of HSCR was mapped to the same
region (28). This location is flanked by genes that in the mouse
flank the piebald mutation, and thus it has been argued that the
two mutant loci are homologous (29).
Endothelin receptor-B
The identity of the piebald/HSCR gene came from a surprising
direction, neither from positional cloning, nor from the
expression pattern of a candidate gene. The three endothelin
peptides (1, 2 and 3) are recognised by two G protein-coupled
heptahelical receptors (A and B). The endothelins were originally
identified as vasoconstrictive agents, but when the receptor-B
(Ednrb) was mutated via homologous recombination in ES cells,
the resulting homozygous mutant mice lacked melanocytes and
had megacolon (30). EDNRB maps to chromosome 13 in
humans, and 14 in mouse, in the region where piebald/HSCR is
located. The ‘knockout’ mutation failed to complement the
classical s alleles and the entire Ednrb gene is deleted from
piebald-lethal mice. The original s mutation has mRNA
expresion reduced by ∼75%. Strictly speaking, none of this
genetic data prove that Ednrb is the piebald gene in mice, as there
could be an effect on a neighbouring gene, but a mutation in the
rat lends convincing evidence. The spotting lethal mutation of rats
results in lack of pigmentation and aganglionic megacolon. These
animals have a deletion within the Ednrb gene, that results in an
aberrantly spliced message and protein truncation (31–33).
Initial analysis of EDNRB mutations in the inbred HSCR
pedigree showed a complicated inheritance pattern (34). The
disease, with or without associated pigmentation defects, was
clearly associated with a missense mutation, W276C (Table 4).
However, some individuals homozygous for the mutation had no
signs of disease, whilst some had only pigmentary defects,
indicating reduced penetrance. Furthermore, a few individuals
had the disease but were wild-type at the EDNRB locus,
indicating additional HSCR genes in the population. Puffenberger
et al. (34) suggest that modifier genes in the population will affect
penetrance, and point to RET as one such modifier Another
candidate modifier would be the ligand of RET, GDNF, and
recent data suggest that variants of this gene do modify the
penetrance of RET-mutant HSCR (35,36). In mice, the
expressivity of the s mutation is clearly under genetic control.
Two different strains of mice with the same mutation have a
substantial difference in the extent of white spotting. A backcross
showed that these differences were controlled by genetic
background. The major locus influencing expressivity maps at or
near the mast cell growth factor (Mgf) gene, which is the gene
affected by spotting mutations called steel, and which encodes the
ligand for the melanocyte survival factor, Kit (37).
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Table 4. Mutations of the endothelin receptor B gene
Species
Mutation
Molecular nature
mouse
s
4× decrease in mRNA; molecular nature not defined
30
rat
sl
sl
complete gene deletion
301 bp deletion: abnormal splicing; two mRNAs, one with frameshift, protein truncation,
one with in frame internal deletion
heterozygous with wild-type gene; large chromosomal deletion; gene deletion
heterozygous with wild-type gene; 1 bp insertion codon 293, frameshift, protein truncation
heterozygous with wild-type gene; 1 bp deletion codon 378, frameshift, protein truncation
heterozygous with wild-type gene; codon 275, TGG→TAG, nonsense mutation, protein truncation
heterozygous with wild-type gene; codon 57, GGT→AGT, Gly→Ser
heterozygous with wild-type gene; codon 305, AGT→AAT, Ser→Asn
heterozygous with wild-type gene; codon 319, GGG→TGG, Arg→Trp
heterozygous with wild-type gene; codon 383, CCA→CTA, Pro→Leu
heterozygous with wild-type or homozygous; codon 276, TGG→TGT, Trp→Cys
30
31–33
115
116
117
116
115
117
115
115
34
homozygous; codon 183, GCC→GGC, Ala→Gly
118
heterozygous with wild-type gene; G→A in 5′ UTR. Causation not proven
115
human
HSCR
HSCR
HSCR (partially penetrant)a
HSCR
HSCR (partially penetrant)a
HSCR (partially penetrant)a
HSCR (partially penetrant)a
HSCR (partially penetrant)a
HSCR (partially penetrant)a;
sometimes pigmentation defect
Waardenburg–Hirschsprung
disease (Shah–Waardenburg)
HSCR (partially penetrant)a
aPenetrance
Ref.
of others not necessarily determined.
Further analysis of the EDNRB gene in HSCR patients may
have clarified the inheritance patterns. Most patients are
heterozygous for a mutant allele. Two sisters have been described
who are homozygous for a missense mutation, A183G (Table 4).
These girls both had pigmentary defects, including a white
forelock, heterochromia irides and deafness (due to lack of inner
ear melanocytes) as well as colonic aganglionosis. Their parents
and a carrier brother were symptom free.
However, at least 12 cases have now been found in which
individuals with short segment colonic aganglionosis are
heterozygous for a deletion, missense, nonsense or frameshift
mutation of EDNRB (Table 4). None of these cases show any
pigmentary defect, and all have inherited the mutation from
parents who have no sign of HSCR. Presumably genetic
background is playing a role in penetrance of the disease. It should
be borne in mind, however, that there has been a case of
monozygotic twins, one of whom has HSCR and one who does
not. There must also be stochastic events during development in
addition to genetic influences that affect the colonic ganglion
population.
Endothelin 3
At the same time as the targeted mutation in mice of the Ednrb
mutation was reported, a knockout of the gene encoding one of
the ligands of this receptor, endothelin-3 (Edn3) was also
described. Mice homozygous for this mutation also have a white
spotting phenotype and aganglionic megacolon. The white
spotting is less severe than results from a loss of Ednrb;
melanocytes remain on the head and hips. The Edn3 gene maps
on distal chromosome 2, where a mutation with a similar
phenotype, lethal spotting (ls) lies. Active endothelins are
processed from large prepropeptides. These are cleaved to
inactive intermediates, big endothelins, which are further acted on
by a specific converting enzyme to produce the 21-residue active
peptide. The Edn3 gene in ls mice contains a missense mutation
within the sequence cleaved to convert the prepropeptide to big
endothelin (Table 5), which blocks formation of the mature
peptide.
Two patients have subsequently been found who are
homozygous for mutations in the human EDN3 gene (Table 5).
Both have total absence of enteric ganglia in the gut, and both
have pigmentary defects including a white forelock, white
eyelashes, white skin patches and deafness. The parents of both
patients had no symptoms, but several relatives in one family (one
of whom was demonstrated to be a carrier) had a range of
pigmentation defects, but did not have HSCR.
Another patient has been found with an apparent EDN3
mutation who has neither HSCR nor pigmentary anomalies.
Instead they have congenital central hypoventilation syndrome
(CCHS), a disease which causes patients to hypoventilate when
asleep. CCHS is often associated with HSCR, but may occur
alone. In this case the mutation, a frameshift truncating the last 41
amino acids of the precursor protein does not appear to be a
polymorphism (it is not found in 260 control chromosomes).
However, it does not affect processing of the prepropeptide in a
cultured cell assay and definitive proof that this mutation causes
CCHS awaits further work.
It is worth noting the differences between mouse and human
inheritance of these mutations. Mice heterozyogus for a loss of
function of either the receptor or the ligand have normal ganglia
throughout their gut (38), whilst human patients carrying one
clear loss of function mutation of the receptor have short segment
colonic aganglionosis, but no pigmentary defects. (Assuming that
the EDNRB allele assessed as normal does not have, for example,
reduced expression.) Patients with a mutation in both EDNRB
alleles have a variable extent of pigmentary defects in association
with aganglionosis; but neither mutation found as homozygous to
date is definitely a complete loss of function. In fact the fairly mild
pigmentary anomalies might suggest some residual receptor
activity is present. The patients homozygous for a clear loss of
function of EDN3 have a very severe aganglionosis and
pigmentation defects, although the unpigmented patches seems to
be less extensive than those seen in lethal-spotted mice.
1618 Human Molecular Genetics, 1997, Vol. 6, No. 10 Review
Table 5. Mutations of the endothelin-3 (EDN3/Edn3) gene
Species
Mutation
Molecular defect
Ref.
mouse
lethal spotting, ls
codon 137, CGG→TGG, Arg→Trp; abolish peptide processing
119
human
Waardenburg–Hirschsprung disease (Shah-Waardenburg)
homozygous; 2 bp deletion, 1 bp insertion, codon 88; frameshift, protein truncation
120
Waardenburg-Hirschsprung disease (Shah-Waardenburg)
homozygousa;
121
congenital central hypoventilation syndrome
heterozygous with wild-type gene; 1 bp insertion codon 188, frameshift, termination
aHeterozygous
codon 159, TGC→TTC, Cys→Phe
122
relatives have partially penetrant pigmentary defects.
Role of Ednrb/Edn3 interaction
Many questions are raised as to the role of this receptor/ligand
interaction in the development of melanocytes and enteric
neurons. Mutations that affect both cell types could be acting in
two ways. Either the interaction is needed in two lineages, both
of neural crest origin, but independently in the lineages after
separation, or the interaction might be needed for the
development, proliferation or survival of a progenitor of both
lineages. Using an in situ probe for the melanoblast lineage,
Pavan and Tilghman (39) showed that no positive cells could be
detected emerging from the neural crest of Ednrb s–l
homozygotes, save for a few near the tail where pigmented
patches were often seen. Two groups have shown that
endothelin-3 in culture acts synergistically with other factors to
increase the number of melanocyte progenitors (40,41). The
interaction is clearly needed early in melanoblast development,
but whether it is needed before the enteric ganglia and
melanoblast lineage diverge is not known. Why some cells escape
the requirement for Edn3 is not known. Edn3 acts in culture to
promote differentiation to a pigmented phenotype and hence can
also act late in development (40).
There is a temporal difference in emergence of the cells from
the crest. In general neuronal progenitor cells leave the crest early,
whilst melanoblasts leave late (42). Kapur et al. (38) used a
transgenic lineage marker to track the migration into the gut by
crest-derived neuroblasts in normal and Ednrb s–l mouse
embryos. Colonisation of the gut occurs in a proximal→distal
(cranial→caudal) direction. Neuroblasts appeared normally in
the proximal gut early in development of mutant embryos but at
embryonic day 12.5 there was a transient arrest, followed by
slower migration to the distal parts of the gut, parts of which were
never colonised. It seems that it is the later colonising cells that
are affected by loss of the endothelin receptor. It may be that, for
some reason, only later emerging cells require the
receptor–ligand interaction to survive or proliferate (and the
melanoblasts, which also emerge late also need it). Alternatively,
all enteric neuroblasts may be affected and have reduced
proliferation or survival, and the diminished number or viability
of precursors is insufficient to affect small intestinal colonisation,
but does affect colonisation of the colon. Very similar results have
been obtained with Edn3 mutant embryos.
Kapur et al. (38) also made a very surprising discovery using
chimaeras between wild-type embryos and Ednrb s–l mutant,
transgene-tagged embryos. Homozygous mutant enteric ganglion
cells, which normally never reach the colon, can be rescued by
wild-type cells, so that in chimaeras they can be seen throughout
the length of the gut. These rescued cells have a deletion of the
receptor gene, and yet must receive a signal from nearby cells that
promotes their development. There are also data to indicate that
Edn3 is produced by the enteric ganglion cells themselves and
acts in an autocrine or paracrine fashion. It seems likely that in
response to Edn3, via the Ednrb, neighbouring cells produce
another intercellular signal which, in turn, acts back on the
ganglion cells. So Ednrb mutant cells could still trigger this signal
from neighbouring cells, and still respond to develop normally.
The nature of this signal is unknown, but one candidate might be
glial-derived neurotrophic factor, GDNF, the ligand for RET,
which is, of course, the other receptor shown genetically to be
required for enteric ganglia colonisation of the gut.
Mayer (43) has also demonstrated, by coculturing mutant
neural tube with wild-type or mutant skin, that Ednrb mutant
melanocytes survive better in wild-type skin. The mutation
therefore is not melanoblast autonomous. A similar intercellular
signalling process downstream of Ednrb may operate on
melanoblasts as in enteric ganglia. A candidate for this signal may
be Mgf, the ligand of the Kit receptor. Reid et al. (40) show that
Edn3 and Mgf act synergistically on neural tube cultures to
increase the number of melanocyte progenitors by >10-fold over
the effect of either alone.
MELANOCYTE-STIMULATING HORMONE
RECEPTOR AND αMSH
Melanocytes can synthesise two different types of melanin: the
black or brown eumelanin and the yellow or red phaeomelanin.
Genetic evidence from several species indicates that the type of
melanin made is determined by response to a family of peptide
hormones known as melanocortins, mediated at the melanocyte
by a G-protein coupled, heptahelical receptor, the melanocortin-1
receptor (Mc1r) (44,45).
Four peptides which derive from the precursor protein,
pro-opiomelanocortin (POMC) have melanocortin activity. In
culture, melanocytes respond to melanocortins by altering their
morphology, increasing expression of a number of melanogenic
enzymes and increasing the activity of tyrosinase enzyme which
leads to an increase in melanin synthesis (46–48). The cells
respond to the peptides differentially, with αMSH being the most
potent, at least in mouse cells, although ACTH, a larger peptide
that includes αMSH at its N-terminus may be more active on
human melanocytes (49). POMC is synthesised in the pituitary
from where circulating melanocortins derive, and melanocortins
in the blood can affect epidermal or follicular melanocytes.
Increased levels of circulating ACTH, as in Addison’s disease in
humans, causes hyperpigmentation, and the increased plasma
αMSH in dopamine D2 receptor mutant mice (50) increases
eumelanin synthesis. However, the pituitary-derived melanocortins may not be the peptides that act on melanocytes under
normal conditions, as animals from which the pituitary has been
removed are normally pigmented. It is likely that POMC
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Figure 1. Amino acid sequence alignment of MC1R from six species (the horse sequence is incomplete). Transmembrane domains 1–7 are indicated by overlining.
Numbering is according to the human sequence. Variant amino acid residues are in bold and underlined. The alterations are as follows. Mouse: S69L, Mc1r tob (dominant
black); E92K, Mc1r so–6J (dominant black); l98P, Mc1r so (dominant black); deletion at codon 183, frameshift (recessive yellow) (53). Cow: L99P, dominant black;
deletion at codon104, frameshift, recessive red (54,55). Horse: S83F, chestnut (56). Fox: C125R, silver (57). Chicken: D92K (plus M92T, A143T, R213C) E (extended
black); C33W (plus D37G) e y (recessive yellow) (58). (Note the chicken variants each occur on a different haplotype background.) Human: V60L; A64S; F76Y; D84E;
V92M; T95M; V97I; A103V; L106Q; R151C; I155T; R160W; R163Q; D294H (59; E.Healy and J.Rees, personal communication).
synthesised locally by keratinocytes is the physiological source of
melanocortins that act on melanocytes in the epidermis and hair
follicle (51).
Mutations of melanocortin receptor-1
There is a family of five melanocortin receptors (44,52), one of
which, Mc1r, is expressed specifically in melanocytes. The hair
of mice is pigmented by both eumelanin and phaeomelanin, the
distribution of which is determined by activity of Mc1r, which in
turn is normally modulated by the action of agouti protein (see
below). A loss of function mutation of Mc1r in mice, recessive
yellow (e) (Fig. 1) results in animals which produce only
phaeomelanin in the follicular melanocytes, and are completely
yellow. Three other mutant alleles in the same gene have the
opposite phenotype; the mice produce predominantly eumelanin.
These dominant mutations result in mice that have constitutive
activation of Mc1r or that are hyper-responsive to melanocortins
(Fig. 1), and all are missense mutations within the second
transmembrane domain of the protein (53).
Recently mutations in MC1R have been found in a number of
other species, although where amino acid substitutions are found,
analysis of the pharmacological function of the changes has not
usually been carried out. In a few cases the mutation is clearly a
loss of function. Red guinea pigs have a deletion of the gene (45)
1620 Human Molecular Genetics, 1997, Vol. 6, No. 10 Review
and red cattle have a frameshift in MC1R, which must inactivate
the protein (54,55) (Fig. 1). The same base change is found in red
Norwegian Cattle and red Holsteins, indicating a common origin
for the mutation in domestic cattle. There is a black variant of
Norwegian Cattle, and the MC1R gene in these animals has a
missense mutation in the second transmembrane domain very
similar to the constitutively active dominant mouse Mc1r variant
(54) (Fig. 1). The chestnut phenotype of horses cosegregates with
a substitution of a conserved amino acid residue in the second
transmembrane domain of MC1R, which is likely to inactivate the
receptor (56).
Surprisingly, the coat colour of the red fox is not due to a variant
of MC1R. However, a semi-dominant variant of the gene, which
produces a constitutively active protein, appears to be responsible
for darkening of the coat of certain fox strains (57) (Fig. 1). There
is an interaction between this allele and a variant at the agouti
locus which modifies the heterozygous phenotype, but
homozygosity for the dominant variant invariably results in the
so-called silver fox phenotype. Variants in the gene also affect
feather pigmentation in chickens. Chicken with a dominant
mutation that gives rise to uniformly black feathers have a
mutation on the second transmembrane domain that results in an
amino acid substitution identical to one of the dominant black
alleles of mouse (58) (Fig. 1), although several other additional
changes are seen throughout the protein. The recessive variant
that produces a uniform yellow/red feather pigmentation is
associated with three missense mutations, two of which are in
codons that are completely conserved throughout all six
published MC1R sequences (58) (Fig. 1). It is likely, though
remains to be proven, that one or both of these mutations cause
loss of MC1R function.
Human variation in MC1R
The involvement of this gene in hair pigmentation variation in so
many species prompted several groups to look for an association
of variants of the human gene with red hair colour. In humans skin
pigmentation shows clear variation that is partially independent of
hair colour. Skin pigmentation in the caucasian population can be
classified into four groups according to the degree of sensitivity to
sunlight; ranging from type I skin which always burns and never
tans, to skin type IV which tans well and rarely burns. All skin
types can be found in association with all hair colours from blond
and fair to dark brown or black, apart from red hair which is
invariably only seen in individuals with skin type I or II. Valverde
et al. (59) found a clear association between red haired individuals
and variants in the MC1R gene (Fig. 1). As all redheads have the
lighter skin types, then the variants could be producing pale skin
rather than red hair and this appears to be the case.
Variants have been found in subjects who have fair or dark hair
and skin type I or II (59–61; E. Healy and J. Rees, personal
communication). In the absence of family studies the genetics are
not as yet clear. Redhaired/pale skinned individuals may be
homozygous or heterozygous for MC1R variants, or possibly
have no variant at all (although it is difficult to prove that a gene
with wild-type sequence is not expressed at a lower level than
normal, for example). There does not seem to be any phenotypic
difference between homozygotes and heterozygotes, and there
may well be interactions with other genes. Barsh (62) has
expressed the data as a ‘relative risk’ for having red hair, being
15-fold increased when heterozygous and 170-fold when
homozygous. It is possible that variation in the gene in humans
results in pale skin, which is a necessary condition for red hair,
which is thus due to the action of other genes whose activity is
only seen on an MC1R variant background.
Perhaps it is significant that not one of the numerous variants
is a frameshift or nonsense mutation which would be a convincing
null. All are missense mutations whose functional consequences
have yet to be determined. Many of the amino acid changes
described thus far are in the second transmembrane domain,
where numerous variants have been seen in other species, albeit
in these cases producing a dominant, darkening phenotype. Some
of the human variants are in positions that are not well conserved
between species, and thus their consequences are difficult to
predict. Other variants are conservative substitutions or indeed
may even introduce an amino acid seen in that location in other
species, and these may be neutral polymorphisms in the human
population. Nevertheless, some changes would appear on the
basis of sequence comparison between species to be functionally
significant, but the key test is to assay the function of the variants.
Two variants have been tested by expression in heterologous cells
and measuring the rise in intracellular cAMP in response to
αMSH, and neither of these (Val92Met and Asp84Glu) show
significant variation from wild-type response (60). The Val92Met
variant has also been assayed for binding affinity by αMSH, and
it appears to have a 5-fold lower affinity for the hormone than
wild-type (63). A more physiological and sensitive assay will be
to use transgenic mice to assay the ability of these variants to
rescue the loss of function Mc1re mutation.
A major risk factor for all forms of skin cancer is the number
of sunburn episodes. Having a paler skin type by definition
increases the chance of sunburn, and thus these skin types confer
an increased risk of cancer. One study has found a highly
significant association between MC1R variants and melanoma
(64). In fact the genetic variants were better predictors of
melanoma risk than skin type. Two explanations might account
for this. Firstly, determination of skin type is a crude
measurement, and this study in some cases used telephone or third
party information to assign skin type. Assay of genetic variation
might then be a more accurate and objective method of assigning
skin type. Alternatively, there may be more than one genetic cause
of pale skin, not all of which increase the risk of melanoma
equally, and MC1R variants may disproportionately increase the
risk. In either case the MC1R genotype may be a useful measure
of an individual’s melanoma risk.
Agouti: an antagonist of melanocortin signalling
One mouse gene for which the genetics is very well understood,
but for which no human variants have been described, is the
agouti gene, which encodes a polypeptide antagonist of Mc1r.
Each mouse dorsal hair is patterned by a band of phaeomelanin
flanked by bands of eumelain which is produced by the
expression of a pulse of agouti protein in the skin midway through
the growth of the hair. The presence of agouti protein blocks the
action of αMSH, and switches melanogenesis from production of
eumelanin (which is dependent on αMSH) to phaeomelanin. The
agouti gene in dorsal skin has a temporally regulated promoter,
synchronised with the hair growth cycle (65). Wild-type, white
bellied agouti, mice have a phaeomelanic ventrum, in which the
agouti gene is constantly expressed through use of a different,
spatially regulated, promoter (66).
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Recessive, loss of function mutations of agouti produce mice
that are uniformly black. One of the old mouse mutations,
nonagouti (a) has a coat that is almost entirely black, but still has
a few yellow hairs. In these mice the agouti gene is not entirely
inactivated, but has a double, or nested, insertion of retroposons
upstream, which inactivates both spatially and temporally
regulated promoters throughout most of the skin, but still allows
expression in certain locations. The a allele can revert by excision
of the retroposons via recombination of the LTRs. If the ‘inner’
retroposon is excised, which leaves behind the outer one, the
ventral specific promoter is restored, but the temporally regulated
promoter is not, giving rise to animals that have a phaeomelanic
belly but a black back. If both retroposons are excised, then both
promoters are restored (67).
Loss of function of the agouti gene can explain recessive black
phenotypes in a number of species, including dogs and cattle, but
molecular data is only available for foxes (57). A deletion of exon
2 of the fox agouti gene produces a semi-dominant phenotype that
darkens the legs and tail, but leaves the rest of the body
phaeomelanic. Homozygous animals have the same silver coat
that homozygotes for the MC1R produce. The agouti and MC1R
genes clearly interact; the double heterozygote is darker than
either single heterozygote, but less dark than either homozygote.
Gain of function, dominant mutations of mouse agouti are
extremely interesting, and are the reason why agouti protein has
attracted a lot of attention recently. Numerous different mouse
alleles exist, but all have promoter rearrangements, deletions or
insertions that result in mice that have misregulation of agouti
protein expression (68). Expression in the skin is permanently on,
so the Mc1r is permanently blocked and the melanocytes make
only phaeomelanin. Expression in one or more other locations has
the result that the animals become obese, presumably because the
protein interferes with some mechanism of weight or feeding
homeostasis (see below).
The mechanism of agouti antagonism in Mc1r signalling is not
understood in detail. Recombinant agouti protein is an antagonist
of the melanocortin induced increase in intracellular cAMP in
heterologous cells that express mouse Mc1r or in melanoma cells
and will prevent the enhanced synthesis of melanin by melanoma
cells in response to αMSH (69–71). There has been debate as to
whether agouti acts to block melanocortin at the receptor or
whether it binds to a different receptor and produces antagonism
intracellularly. The evidence is now strong that action on pigment
cells is through Mc1r. Agouti protein can be shown directly to
bind to the receptor (69,71). On the other hand, agouti protein can
elicit a response in melanoma cells that is independent of αMSH.
Cells treated with the recombinant protein have dose-dependent
growth inhibition, clearly showing an effect of agouti that is not
due to antagonism of Mc1r. However, this activity is also
mediated through Mc1r, as melanoma cells that lack the receptor
do not show the response (71). The likeliest explanation is that
agouti is an inverse agonist of Mc1r; that is, it can compete with
αMSH for binding to the receptor and on binding acts to reduce
the basal (unstimulated) signalling from Mc1r.
Recessive yellow mice (Mc1r deficient) are not identical to
dominant yellow animals (over-expressing agouti); they are a
darker shade. This is consistent with agouti having an effect on
melanocytes that is more than simply blocking αMSH. A genetic
prediction which ensues is that a double mutant, both lacking
Mc1r and overexpressing agouti will have a phenotype the same
as the recessive yellow animals, because the overexpressed agouti
protein cannot act on Mc1r deficient melanocytes.
Agouti protein and obesity
Numerous different, dominant overexpressing, alleles of the
mouse agouti gene all demonstrate obesity (65,68). Furthermore,
transgenic mice, in which the agouti gene is expressed from a
ubiquitous promoter are also obese (72). The simplest model to
explain this is that agouti protein is antagonising another
melanocortin receptor, which alters the regulation of weight
control or feeding. A corollary is that there might be other
proteins, related to agouti, that are expressed in the brain that are
the normal antagonist of these receptors.
Agouti has been shown to antagonise other members of the
melanocortin receptor family. Mc3r and Mc5r are not affected by
concentrations of agouti protein that antagonise Mc1r. However
agouti is a potent antagonist of the brain-expressed receptor Mc4r
(69). The role of Mc4r in regulating mouse feeding behaviour has
been elegantly demonstrated by both genetic and pharmacological means. An ES-cell mediated gene disruption of Mc4r,
when homozygous, results in mice that are hyperphagic and obese
(73). The synthetic cyclic melanocortin compound SHU9119 is
a potent antagonist of αMSH binding to Mc4r, but not to Mc3r.
When normal mice are injected in the cerebral ventricles with
SHU9119 they respond by increasing food intake (74). By
contrast, a very closely related compound, MTII has the reverse
effect, being a potent agonist of Mc4r, but less so of Mc3r. When
MTII is injected intracerebrally, feeding is inhibited (74).
If modulating Mc4r activity by artificial means can have these
effects on feeding, is there a natural neuropeptide that has the
same effect? By screening the sequence database Shutter et al.
(75) identified a protein distantly related to agouti (ART), that is
expressed in the mouse brain in a similar location to POMC and
to neuropeptide Y, another peptide hormone that can influence
feeding behaviour. ART may be the natural antagonist of Mc4r
and may be involved in regulation of feeding and weight.
Coming to understand the nature of a number of classical
mouse mutations has led to potentially very important insights
into the regulation of feeding behaviour. All the mutations
discussed in this review not only have proved useful models for
the understanding of human genetic disease, but their pleiotropic
phenotypes give invaluable insight into normal physiological
processes.
REFERENCES
1. Jackson, I. J. (1994) Molecular and developmental genetics of mouse coat
color. Annu. Rev. Genet. 28, 189–217.
2. Spritz, R. A. (1994) Molecular-genetics of oculocutaneous albinism. Hum.
Mol. Genet. 3, 1469–1475.
3. Zhou, B.-K., Boissy, R. E., Pifko-Hirst, S., Moran, D., and Orlow, S. J. (1993)
Lysosome-Associated Membrane Protein-1 (LAMP-1) is the melanocyte
vesicular membrane glycoprotein band II. J. Invest. Dermatol. 100, 110–114.
4. Diment, S., Eidelman, M., Rodriguez, G. M., and Orlow, S. J. (1995)
Lysosomal hydrolases are present in melanosomes and are elevated in
melanising cells. J. Biol. Chem. 270, 4213–4215.
5. Winder, A. J., Wittbjer, A., Rosengren, E., and Rorsman, H. (1993) The
mouse brown (b) locus protein has dopachrome tautomerase activity and is
located in lysosomes in transfected fibroblasts. J. Cell Sci. 106, 153–166.
6. Novak, E. K., Hui, S. W., and Swank, R. T. (1984) Platelet storage pool
deficiency in mouse pigment mutations associated with 7 distinct
genetic-loci. Blood 63, 536–544.
1622 Human Molecular Genetics, 1997, Vol. 6, No. 10 Review
7. Novak, E. K., Sweet, H. O., Prochazka, M., Parentis, M., Soble, R.,
Reddington, M., Cairo, A., and Swank, R. T. (1988) Cocoa - a new mouse
model for platelet storage pool deficiency. Brit. J. Haematol. 69, 371–378.
8. Swank, R. T., Sweet, H. O., Davisson, M. T., Reddington, M., and Novak, E.
K. (1991) Sandy - a new mouse model for platelet storage pool deficiency.
Genet. Res. 58, 51–62.
9. Swank, R. T., Reddington, M., Howlett, O., and Novak, E. K. (1991) Platelet
storage pool deficiency associated with inherited abnormalities of the
inner-ear in the mouse pigment mutants muted and mocha. Blood 78,
2036–2044.
10. Pastural, E., Barrat, F.J., Dufourcq-Lagelouse, R., Certain, S., Sanal, O.,
Jabado, N., Seger, R., Criscelli, C., Fischer, A. and de Saint Basile, G. (1997)
Griscelli disease maps to chromosome 15q21 and is associated with
mutations in the Myosin Va gene. Nature Genet., 16, 289–292.
11. Perou, C. M., and Kaplan, J. (1993) Complementation analysis of
Chediak-Higashi-Syndrome - the same gene may be responsible for the
defect in all patients and species. Somatic Cell Mol. Genet. 19, 459–468.
12. Jenkins, N.A., Justice, M.J., Gilbert, D.J., Chu, M.L. and Copeland, N;G.
(1991) Nidogen entactin (Nid) maps to the proximal end of mouse
chromosome 13, linked to beige, and identifies a new region of homology
between mouse and human chromosomes. Genomics 9, 401–403.
13. Barrat, F. J., Auloge, L., Pastural, E., Lagelouse, R. D., Vilmer, E., Cant, A. J.,
Weissenbach, J., Lepaslier, D., Fischer, A., and Desaintbasile, G. (1996)
Genetic and physical mapping of the Chediak-Higashi-Syndrome on
chromosome 1q42–43. Am. J. Hum. Genet. 59, 625–632.
14. Fukai, K., Oh, J., Karim, M. A., Moore, K. J., Kandil, H. H., Ito, H., Burger, J.,
and Spritz, R. A. (1996) Homozygosity mapping of the gene for ChediakHigashi-Syndrome to chromosome 1q42–q44 in a segment of conserved
synteny that includes the mouse beige locus (bg). Am. J. Hum. Genet. 59,
620–624.
15. Perou, C. M., Moore, K.K., Nagle, D.L., Misumi, D.J., Woolf, E.A., McGrail,
S.H., Holmgren, L., Brody, T.H., Dussault, B.J. Jr., Monroe, C.A., Duyk, G.M.,
Pryor, T.H., Li, L., Justice, M.J., and Kaplan, J. (1996) Identification of the
murine beige gene by YAC complementation and positional cloning. Nature
Genet. 13, 313–308.
16. Barbosa, M. D. F. S., Nguyen, Q. A., Tchernev, V. T., Ashley, J. A., Detter, J.
C., Blaydes, S. M., Brandt, S. J., Chotai, D., Hodgman, C., Solari, R. C. E.,
Lovett, M., and Kingsmore, S. F. (1996) Identification of the homologous
beige and Chediak-Higashi-Syndrome genes. Nature 382, 262–265.
17. Nagle, D. L., Karim, M. A., Woolf, E. A., Holmgren, L., Bork, P., Misumi, D.
J., McGrail, S. H., Dussault, B. J., Perou, C. M., Boissy, R. E., Duyk, G. M.,
Spritz, R. A., and Moore, K. J. (1996) Identification and mutation analysis of
the complete gene for Chediak-Higashi-Syndrome. Nature Genet. 14,
307–311.
18. Karim, M.A., Nagle, D.L., Kandil, H.H., Burger, J., Moore, K.J. and Spritz,
R.A. (1997) Mutations in the Chediak-Higashi syndrome gene (CHS1)
indicate requirement for the complete 3801 amino acid CHS protein. Hum.
Mol. Genet. 6, 1087–1089.
19. Barbosa, M.D.F.S., Barrat, F.J., Tchernev, V.T., Nguyen, Q.A., Mishra, V.S.,
Colman, S.D., Pastural, E., Dufourcq-Lagelouse, R., Fischer, A., Holcombe,
R.F., Wallace, M.R., Brandt, S.J., de Saint Basile, G. and Kingsmore, S.F.
(1997) Identification of mutations in two major mRNA isoforms of the
Chediak–Higashi syndrome gene in human and mouse. Hum. Mol. Genet. 6,
1091–1098.
20. Fukai, K., Oh, J., Frenk, E., Almodovar, C., and Spritz, R. A. (1995) Linkage
disequilibrium mapping of the gene for Hermansky-Pudlak Syndrome to
chromosome 10q23.1–q23.3. Hum. Mol. Genet. 4, 1665–1669.
21. Oh, J., Bailin, T., Fukai, K., Feng, G. H., Ho, L. L., Mao, J. I., Frenk, E.,
Tamura, N., and Spritz, R. A. (1996) Positional cloning of a gene for
Hermansky-Pudlak Syndrome, a disorder of cytoplasmic organelles. Nature
Genet. 14, 300–306.
22. Feng, G. H., Bailin, T., Oh, J., and Spritz, R. A. (1997) Mouse pale ear (ep) is
homologous to human Hermansky-Pudlak syndrome and contains a rare
AT-AC intron. Hum. Mol. Genet. 6, 793–797.
23. Ramsay, M. (1996) Protein trafficking violations. Nature Genet. 14, 242–245.
24. Tassabehji, M., Newton, V. E., Liu, X.-Z., Brady, A., Donnai, D.,
Krajewska-Walasek, M., Murday, V., Norman, A., Obersztyn, E., Reardon,
W., Rice, J. C., Trembath, R., Wieacker, P., Whiteford, M., Winter, R., and
Read, A. P. (1995) The mutational spectrum in Waardenburg syndrome. Hum.
Mol. Genet. 4, 2131–2137.
25. Epstein, D. J., Vekemans, M., and Gros, P. (1991) Splotch (Sp 2H), a mutation
affecting development of the mouse neural tube, shows a deletion within the
paired homeodomain of Pax-3. Cell 67, 767–774.
26. Goulding, M., Sterrer, S., Fleming, J., Balling, R., Nadeau, J., Moore, K. J.,
Brown, S. D. M., Steel, K. P., and Gruss, P. (1993) Analysis of the Pax-3 gene
in the mouse mutant Splotch. Genomics 17, 355–363.
27. Chakravarti, A. (1996) Endothelin-receptor mediated signalling in
Hirschsprung Disease. Hum. Mol. Genet. 5 303–307.
28. Puffenberger, E. G., Kauffman, E. R., Bolk, S., Matise, T. C., Washington, S.
S., Angrist, M., Weissenbach, J., Garver, K. L., Mascari, M., Ladda, R.,
Slaugenhaupt, S. A., and Chakravarti, A. (1994) Identity-by-descent and
association mapping of a recessive gene for Hirschsprung disease on
human-chromosome 13q22. Hum. Mol. Genet. 3, 1217–1225.
29. Bouchard, B., Delmarmol, V., Jackson, I. J., Cherif, D., and Dubertret, L.
(1994) Molecular characterization of a human tyrosinase-related-protein-2
cDNA - patterns of expression in melanocytic cells. Eur. J. Biochem. 219,
127–134.
30. Hosoda, K., Hammer, R. E., Richardson, J. A., Baynash, A. G., Cheung, J. C.,
Giaid, A., and Yanagisawa, M. (1994) Targeted and natural (piebald-lethal)
mutations of endothelin-b receptor gene produce megacolon associated with
spotted coat color in mice. Cell 79, 1267–1276.
31. Gariepy, C. E., Cass, D. T., and Yanagisawa, M. (1996) Null mutation of
endothelin receptor-type-b gene in spotting lethal rats causes aganglionic
megacolon and white coat color. Proc. Natl. Acad. Sci. USA 93, 867–872.
32. Ceccherini, I., Zhang, A. L., Matera, I., Yang, G. C., Devoto, M., Romeo, G.,
and Cass, D. T. (1995) Interstitial deletion of the endothelin-b receptor gene in
the spotting lethal (sl) rat. Hum. Mol. Genet. 4, 2089–2096.
33. Kunieda, T., Kumagi, T., Tsuji, T., Ozaki, T., Karaki, H., and Ikadai, H. (1996)
A mutation in endothelin-B receptor gene causes myenteric agangliosis and
coat color spotting in rats. DNA Res. 3, 101–105.
34. Puffenberger, E. G., Hosoda, K., Washington, S. S., Nakao, K., Dewit, D.,
Yanagisawa, M., and Chakravarti, A. (1994) A missense mutation of the
endothelin-b receptor gene in multigenic hirschsprungs-disease. Cell 79,
1257–1266.
35. Angrist, M., Bolk, S., Halushka, M., Lapchak, P. A., and Chakravarti, A.
(1996) Germline mutations in glial cell line-derived neurotrophic factor
(GDNF) and RET in a Hirschsprung diease patient. Nature Genet. 14,
341–343.
36. Salomon, R., Attie, T., Pelet, A., Bidaud, C., Eng, C., Amiel, J., Sarnacki, S.,
Goulet, O., Ricour, C., Nihoul-Fekete, C., Munnich, A., and Lyonnet, S.
(1996) Germline mutations of the RET ligand GDNF are not sufficient to
cause Hirschsprung disease. Nature Genet. 14, 345–347.
37. Pavan, W. J., Mac, S., Cheng, M., and Tilghman, S. M. (1995) Quantitative
trait loci that modify the severity of spotting in piebald mice. Genome Res. 5,
29–41.
38. Kapur, R. P., Sweetser, D. A., Doggett, B., Siebert, J. R., and Palmiter, R. D.
(1995) Intercellular signals downstream of endothelin receptor-b mediate
colonization of the large-intestine by enteric neuroblasts. Development 121,
3787–3795.
39. Pavan, W. J., and Tilghman, S. M. (1994) Piebald lethal acts early to disrupt
the development of neural crest-derived melanocytes. Proc. Natl. Acad. Sci.
USA 91, 7159–7163.
40. Reid, K., Turnley, A. M., Maxwell, G. D., Kurihara, Y., Kurihara, H., Bartlett,
P., and Murphy, M. (1996) Multiple roles for endothelin in melanocyte
development: Regulation of progenitor number and stimulation of
differentiation. Development 122, 3911–3919.
41. Lahav, R., Ziller, C., Dupin, E., and Ledouarin, N. M. (1996) Endothelin-3
promotes neural crest cell-proliferation and mediates a vast increase in
melanocyte number in culture. Proc. Natl. Acad. Sci. USA 93, 3892–3897.
42. Wehrlehaller, B., and Weston, J. A. (1995) Soluble and cell-bound forms of
steel factor activity play distinct roles in melanocyte precursor dispersal and
survival on the lateral neural crest migration pathway. Development 121,
731–742.
43. Mayer, T. C. (1977) Enhancement of melanocyte development from piebald
neural crest by a favourable tissue environment. Dev. Biol. 56, 255–262.
44. Cone, R. D., Mountjoy, K. G., Robbins, L. S., Nadeau, J. H., Johnson, K. R.,
Rosellirehfuss, L., and Mortrud, M. T. (1993) Cloning and
functional-characterization of a family of receptors for the melanotropic
peptides. Ann. NY Acad. Sci. 680, 342–363.
45. Cone, R. D., Lu, D., Koppula, S., Vage, D. I., Klungland, H., Boston, B.,
Chen, W., Orth, D. N., Pouton, C., and Kesterson, R. A. (1996) The
melanocortin receptors: Agonists, antagonists, and the hormonal control of
pigmentation. Recent Prog. Hormone Res. 51, 287–317.
46. Burchill, S. A., Ito, S., and Thody, A. J. (1993) Effects of melanocyte-stimulating hormone on tyrosinase expression and melanin synthesis in
hair follicular melanocytes of the mouse. J. Endocrinol. 137, 189–195.
1623
Human Molecular
Genetics,
1997,1994,
Vol. Vol.
6, No.
Review
1623
Nucleic Acids
Research,
22,10
No.
1
47. Hunt, G., Todd, C., Cresswell, J. E., and Thody, A. J. (1994) Alpha-melanocyte-stimulating hormone and its analog Nle(4)DPhe(7)alpha-MSH affect
morphology, tyrosinase activity and melanogenesis in cultured human
melanocytes. J. Cell Sci. 107, 205–211.
48. Suzuki, I., Cone, R. D., Im, S., Nordlund, J., and Abdelmalek, Z. A. (1996)
Binding of melanotropic hormones to the melanocortin receptor MC1R on
human melanocytes stimulates proliferation and melanogenesis.
Endocrinology 137, 1627–1633.
49. Hunt, G., Todd, C., Kyne, S., and Thody, A. J. (1994) ACTH stimulates
melanogenesis in cultured human melanocytes. J. Endocrinol. 140, R1–R3.
50. Yamaguchi, H., Aiba, A., Nakamura, K., Nakao, K., Sakagami, H., Goto, K.,
Kondo, H., and Katsuki, M. (1996) Dopamine D2 receptor plays a critical role
in cell proliferation and proopiomelanocortin expression in the pituitary.
Genes Cells 1, 253–268.
51. Wintzen, M., Yaar, M., Burbach, J. P. H., and Gilchrest, B. A. (1996)
Proopiomelanocortin gene-product regulation in keratinocytes. J. Invest.
Dermatol. 106, 673–678.
52. Mountjoy, K. G., Robbins, L. S., Mortrud, M. T., and Cone, R. D. (1992) The
cloning of a family of genes that encode the melanocortin receptors. Science
257, 1248–1251.
53. Robbins, L. S., Nadeau, J. H., Johnson, K. R., Kelly, M. A., Roselli-Rehfuss,
L., Baack, E., Mountjoy, K. G., and Cone, R. D. (1993) Pigmentation
phenotypes of variant extension locus alleles result from point mutations that
alter receptor function. Cell 72, 827–834.
54. Klungland, H., Vage, D. I., Gomezraya, L., Adalsteinsson, S., and Lien, S.
(1995) The role of melanocyte-stimulating hormone (MSH) receptor in
bovine coat color determination. Mammalian Genome 6, 636–639.
55. Joerg, H., Fries, H. R., Meijerink, E., and Stranzinger, G. F. (1996) Red coat
color in holstein cattle is associated with a deletion in the MSHR gene.
Mammalian Genome 7, 317–318.
56. Marklund, L., Johansson Moller, M., Sandberg, K., and Andersson, L. (1996)
A missense mutation in the gene for melanocyte-stimulating hormone
receptor (MC1R) is associated with chestnut coat color in horses. Mammalian
Genome 7, 895–899.
57. Vage, D. I., Lu, D., Klungland, H., Lien, S., Adalsteinsson, S., and Cone, R. D.
(1997) A non-epistatic interaction of agouti and extension in the fox, Vulpes
vulpes. Nature Genet. 15, 311–316.
58. Takeuchi, S., Suzuki, H., Yabuuchi, M., and Takahashi, S. (1996) A possible
involvement of melanocortin 1-receptor in regulating feather color pigmentation in the chicken. Biochim. Biophys. Acta Gene Struct. Exp. 1308,
164–168.
59. Valverde, P., Healy, E., Jackson, I., Rees, J. L., and Thody, A. J. (1995)
Variants of the melanocyte-stimulating hormone-receptor gene are associated
with red hair and fair skin in humans. Nature Genet. 11, 328–330.
60. Koppula, S. V., Robbins, L. S., Lu, D., Baack, E., White, C. R. J., Swanson, N.
A., and Cone, R. D. (1997) Identification of common polymorphisms in the
coding sequence of human MSH receptor (MC1R) with possible biological
effects. Hum. Mut. 9, 30–36.
61. Box, N.F., Wyeth, J.R., O’Gorman, L.E., Martin, N.G. and Sturm, R.A.
(1997) Characterisation of melanocyte-stimulating hormone receptor alleles
in twins of red hair colour. Hum. Mol. Genet., 6, in press.
62. Barsh, G. S. (1996) The genetics of pigmentation - from fancy genes to
complex traits. Trends Genet. 12, 299–305.
63. Xu, X. L., Thornwall, M., Lundin, L. G., and Chhajlani, V. (1996) Val92met
variant of the melanocyte-stimulating hormone-receptor gene. Nature Genet.
14, 384.
64. Valverde, P., Healy, E., Sikkink, S., Haldane, F., Thody, A. J., Carothers, A.,
Jackson, I. J., and Rees, J. L. (1996) The Asp84Glu variant of the
melanocortin-1 receptor (MC1R) is associated with melanoma. Hum. Mol.
Genet. 5, 1663–1666.
65. Bultman, S. P., Michaud, E. J., and Woychik, R. P. (1992) Molecular
characterisation of the mouse agouti locus. Cell 71, 1–20.
66. Vrieling, H., Duhl, D. M. J., Millar, S. E., Miller, K. A., and Barsh, G. S.
(1994) Differences in dorsal and ventral pigmentation result from regional
expression of the mouse agouti gene. Proc. Natl. Acad. Sci. USA 91,
5667–5671.
67. Bultman, S. J., Klebig, M. L., Michaud, E. J., Sweet, H. O., Davisson, M. T.,
and Woychik, R. P. (1994) Molecular analysis of reverse mutations from
nonagouti (a) to black-and-tan (a t) and white-bellied agouti (Aw) reveals
alternative forms of agouti transcripts. Genes Dev. 8, 481–490.
68. Duhl, D. M. J., Vrieling, H., Miller, K. A., Wolff, G. L., and Barsh, G. S.
(1994) Neomorphic agouti mutations in obese yellow mice. Nature Genet. 8,
59–65.
69. Lu, D. S., Willard, D., Patel, I. R., Kadwell, S., Overton, L., Kost, T., Luther,
M., Chen, W. B., Woychik, R. P., Wilkison, W. O., and Cone, R. D. (1994)
Agouti protein is an antagonist of the melanocyte-stimulating-hormone
receptor. Nature 371, 799–802.
70. Blanchard, S. G., Harris, C. O., Ittoop, O. R. R., Nichols, J. S., Parks, D. J.,
Truesdale, A. T., and Wilkison, W. O. (1995) Agouti antagonism of
melanocortin binding and action in the b16f10 murine melanoma cell-line.
Biochemistry 34, 10406–10411.
71. Siegrist, W., Willard, D. H., Wilkison, W. O., and Eberle, A. N. (1996) Agouti
protein inhibits growth of B16 melanoma-cells in-vitro by acting through
melanocortin receptors. Biochem. Biophys. Res. Comm. 218, 171–175.
72. Klebig, M. L., Wilkinson, J. E., Geisler, J. G., and Woychik, R. P. (1995)
Ectopic expression of the agouti gene in transgenic mice causes obesity,
features of type-II diabetes, and yellow fur. Proc. Natl. Acad. Sci. USA 92,
4728–4732.
73. Huscar, D., Lynch, C. A., Fairchild-Huntress, V., Dunmore, J. H., Fang, Q.,
Berkemeier, L. R., Gu, W., Kesterson, R. A., Boston, B. A., Cone, R. D.,
Smith, F. J., Campfield, L. A., Burn, P., and Lee, F. (1997) Targeted disruption
of the melanocortin-4 receptor results in obesity in mice. Cell 88, 131–141.
74. Fan, W., Boston, B., Kesterson, R. A., Hruby, V. J., and Cone, R. D. (1997)
Role of melanocortinergic neurons in feeding and the agouti obesity
syndrome. Nature 385, 165–168.
75. Shutter, J. R., Graham, M., Kinsey, A. C., Scully, S., Luthy, R., and Stark, K.
L. (1997) Hypothalamic expression of ART, a novel gene related to agouti is
up-regulated in obese and diabetic mutant mice. Genes Dev. 11, 593–602.
76. Hodgkinson, C. A., Moore, K. J., Nakayama, A., Steingrimsson, E.,
Copeland, N. G., Jenkins, N. A., and Arnheiter, H. (1993) Mutations at the
mouse microphthalmia locus are associated with defects in a gene encoding a
novel basic-helix-loop-helix-zipper protein. Cell 74, 395–404.
77. Jackson, I. J., and Raymond, S. (1994) Manifestations of microphthalmia.
Nature Genet. 8, 209–210.
78. Nocka, K., Tan, J. C., Chiu, E., Chu, T. Y., Ray, P., Traktman, P., and Besmer,
P. (1990) Molecular bases of dominant negative and loss of function
mutations at the murine c-kit/white spotting locus: W 37, W v, W 41 and W.
EMBO J. 9, 1805–1813.
79. Reith, A. D., Rottapel, R., Giddens, E., Brady, C., Forrester, L., and Bernstein,
A. (1990) W mutant mice with mild or severe developmental defects contain
distinct point mutations in the kinase domain of the c-kit receptor. Genes Dev.
4, 390–400.
80. Spritz, R. A., Holmes, S. A., Ramesar, R., Greenberg, J., Curtis, D., and
Beighton, P. (1992) Mutations of the kit (mast stem-cell growth-factor
receptor) protooncogene account for a continuous range of phenotypes in
human piebaldism. Am. J. Hum. Genet. 51, 1058–1065.
81. Giebel, L. B., and Spritz, R. A. (1991) Mutation of the KIT (mast/stem cell
growth factor receptor) protooncogene in human piebaldism. Proc. Natl.
Acad. Sci. USA 88, 8696–8699.
82. Moller, M. J., Chaudhary, R., Hellmen, E., Hoyheim, B., Chowdhary, B., and
Andersson, L. (1996) Pigs with the dominant white coat color phenotype
carry a duplication of the kit gene encoding the mast/stem cell-growth
factor-receptor. Mammalian Genome 7, 822–830.
83. Zsebo, K. M., Williams, D. A., Geissler, E. N., Broudy, V. C., Martin, F. H.,
Atkins, H. L., Hsu, R.-Y., Birkett, N. C., Okino, K. H., Murdock, D. C.,
Jacobsen, F. W., Langley, K. E., Smith, K. A., Takeishi, T., Cattanach, B. M.,
Galli, S. J., and Suggs, S. V. (1990) Stem cell factor is encoded at the Steel
locus of the mouse and is the ligand for the c-kit tyrosine kinase receptor. Cell
63, 213–224.
84. Copeland, N. G., Gilbert, D. J., Cho, B. C., Donovan, P. J., Jenkins, N. A.,
Cosman, D., Anderson, D., Lyman, S. D., and Williams, D. E. (1990) Mast
cell growth factor maps near the Steel locus on mouse chromosome 10 and is
deleted in a number of steel alleles. Cell 63, 175–183.
85. Huang, E., Nocka, K., Beier, D. R., Chu, T.-Y., Buck, J., Lahm, H.-W.,
Wellner, D., Leder, P., and Besmer, P. (1990) The hematopoietic growth factor
KL is encoded by the Sl locus and is the ligand of the c-kit receptor, the gene
product of the W locus. Cell 63, 225–233.
86. Duhl, D. M. J., Stevens, M. E., Vrieling, H., Saxon, P. J., Miller, M. W.,
Epstein, C. J., and Barsh, G. S. (1994) Pleiotropic effects of the mouse lethal
yellow (Ay) mutation explained by deletion of a maternally expressed gene
and the simultaneous production of agouti fusion RNAs. Development 120,
1695–1708.
87. Mercer, J. A., Seperack, P. K., Strobel, M. C., Copeland, N. G., and Jenkins,
N. A. (1991) The murine dilute coat colour locus encodes a novel myosin
heavy chain. Nature 348, 709–713.
1624 Human Molecular Genetics, 1997, Vol. 6, No. 10 Review
88. Titus, M. A. (1993) From fat yeast and nervous mice to brain myosin-V. Cell
75, 9–11.
89. Cecchi, C., Biasotto, M., Tosi, M., and Avner, P. (1997) The mottled mouse as
a model for human Menkes disease: Identification of mutations in the Atp7a
gene. Hum. Mol. Genet. 6, 425–433.
90. Reed, V., and Boyd, Y. (1997) Mutation analysis provides additional proof
that mottled is the mouse homologue of Menkes disease. Hum. Mol. Genet. 6,
417–423.
91. Tumer, Z., Lund, C., Tolshave, J., Vural, B., Tonnesen, T., and Horn, N.
(1997) Identification of point mutations in 41 unrelated patients affected with
Menkes disease. Am. J. Hum. Genet. 60, 63–71.
92. Yuan, D. S., Stearman, R., Dancis, A., Dunn, T., Beeler, T., and Klausner, R.
D. (1995) The Menkes-Wilson disease gene homolog in yeast provides
copper to a ceruloplasmin-like oxidase required for iron uptake. Proc. Natl.
Acad. Sci. USA 92, 2632–2636.
93. Das, S., Levinson, B., Vulpe, C., Whitney, S., Gitschier, J., and Packman, S.
(1995) Similar splicing mutations of the Menkes-mottled copper-transporting
ATPase gene in occipital horn syndrome and the blotchy mouse. Am. J. Hum.
Genet. 56, 570–576.
94. Fukai, K., Holmes, S. A., Lucchese, N. J., Siu, V. M., Weleber, R. G., Schnur,
R. E., and Spritz, R. A. (1995) Autosomal recessive ocular albinism
associated with a functionally significant tyrosinase gene polymorphism.
Nature Genet. 9, 92–95.
95. Koga, A., Inagaki, H., Bessho, Y., and Hori, H. (1995) Insertion of a novel
transposable element in the tyrosinase gene is responsible for an albino
mutation in the medaka fish, Oryzias latipes. Mol. Gen. Genet. 249, 400–405.
96. Oetting, W. S., and King, R. A. (1992) Molecular analysis of type I-A
(tyrosinase-negative) oculocutaneous albinism. Hum. Genet. 90, 258–262.
97. Oetting, W. S., Brilliant, M. H., and King, R. A. (1996) The clinical spectrum
of albinism in humans. Mol. Med. Today 2, 330–335.
98. Zdarsky, E., Favor, J., and Jackson, I. J. (1990) The molecular basis of brown,
an old mouse mutation, and of a revertant to wild-type. Genetics 126,
443–449.
99. Jackson, I. J., Chambers, D., Rinchik, E. M., and Bennett, D. C. (1990)
Characterisation of TRP-1 mRNA levels in dominant and recessive
mutations at the mouse brown locus. Genetics 126, 451–459.
100.Boissy, R. E., Zhao, H. Q., Oetting, W. S., Austin, L. M., Wildenberg, S. C.,
Boissy, Y. L., Zhao, Y., Sturm, R. A., Hearing, V. J., King, R. A., and
Nordlund, J. J. (1996) Mutation in and lack of expression of tyrosinaserelated protein-1 (TRP-1) in melanocytes from an individual with brown
oculocutaneous albinism - a new subtype of albinism classified as oca3. Am.
J. Hum. Genet. 58, 1145–1156.
101.Sjoling, A., Klingalevan, K., and Levan, G. (1996) Sublocalization of the rat
brown gene (b=Tyrp1) by linkage mapping. Mammalian Genome 7,
710–711.
102.Jackson, I. J., Chambers, D. M., Tsukamoto, K., Copeland, N. G., Gilbert, D.
J., Jenkins, N. A., and Hearing, V. J. (1992) A second tyrosinase-related
protein, TRP-2, maps to and is mutated at the mouse slaty locus. EMBO J. 11,
527–535.
103.Budd, P. S., and Jackson, I. J. (1995) Structure of the mouse Tyrosinaserelated protein-2 Dopachrome Tautomerase (Tyrp2/Dct) gene and sequence
of 2 novel slaty alleles. Genomics 29, 35–43.
104.Rinchik, E. M., Bultman, S. J., Horsthemke, B., Lee, S.-T., Strunk, K. M.,
Spritz, R. A., Avidano, K. M., Jong, M. T. C., and Nicholls, R. D. (1993) A
gene for the mouse pink-eyed dilution locus and for human type II
oculcutaneous albinism. Nature 361, 71–76.
105.Durhampierre, D., Gardner, J. M., Nakatsu, Y., King, R. A., Francke, U.,
Ching, A., Aquaron, R., Delmarmol, V., and Brilliant, M. H. (1994) African
origin of an intragenic deletion of the human-p gene in tyrosinase positive
oculocutaneous albinism. Nature Genet. 7, 176–179.
106.Lee, S. T., Nicholls, R. D., Schnur, R. E., Guida, L. C., Lukuo, J., Spinner, N.
B., Zackai, E. H., and Spritz, R. A. (1994) Diverse mutations of the p-gene
among African-Americans with type-II (tyrosinase-positive) oculocutaneous
albinism (oca2) Hum. Mol. Genet. 3, 2047–2051.
107.Stevens, G., Vanbeukering, J., Jenkins, T., and Ramsay, M. (1995) An
intragenic deletion of the p-gene is the common mutation causing
tyrosinase-positive oculocutaneous albinism in southern African negroids.
Am. J. Hum. Genet. 56, 586–591.
108.Oetting, W. S., Brilliant, M. H., Gardiner, J. M., Fryer, J. P., and King, R. A.
(1995) Mutations and polymorphisms of the human p-gene associated with
p-related oculocutaneous albinism (OCA2) Am. J. Hum. Genet. 57(4 Ss),
1432.
109.Kwon, B. S., Halaban, R, Ponnazhagan, S., Kim, K., Chintamaneni, C.,
Bennett, D., and Pickard, R. T. (1995) Mouse silver mutation is caused by a
single base insertion in the putative cytoplasmic domain of Pmel17. Nucleic
Acids Res. 23, 154–158.
110.Kwon, B. S., Chintamaneni, C., Kozak, C. A., Copeland, N. G., Gilbert, D. J.,
Jenkins, N. A., Barton, D., Francke, U., Kobayashi, Y., and Kim, K. K. (1991)
A melanocyte-specific gene, Pmel17, maps near the silver coat color locus on
mouse chromosome 10 and is in a syntenic region on human chromosome 12.
Proc. Natl. Acad. Sci. USA 88, 9228–9232.
111. Bassi, M. T., Schiaffino, M. V., Renieri, A., Denigris, F., Galli, L., Bruttini, M.,
Gebbia, M., Bergen, A. A. B., Lewis, R. A., and Ballabio, A. (1995) Cloning
of the gene for ocular albinism type-1 from the distal short arm of the
X-chromosome. Nature Genet. 10, 13–19.
112.Schiaffino, M. V., Bassi, M. T., Galli, L., Renieri, A., Bruttini, M., Denigris, F.,
Bergen, A. A. B., Charles, S. J., Yates, J. R. W., Meindl, A., Lewis, R. A.,
King, R. A., and Ballabio, A. (1995) Analysis of the OA1 gene reveals
mutations in only 1/3 of patients with X-linked ocular albinism. Hum. Mol.
Genet. 4, 2319–2325.
113.Bassi, M. T., Incerti, B., Easty, D. J., Sviderskaya, E. V., and Ballabio, A.
(1996) Cloning of the murine homolog of the ocular albinism type-1 (OA1)
gene - sequence, genomic structure, and expression analysis in pigment-cells.
Genome Res. 6, 880–885.
114.Newton, J. M., Orlow, S. J., and Barsh, G. S. (1996) Isolation and
characterization of a mouse homolog of the X-linked ocular albinism (OA1)
gene. Genomics 37, 219–225.
115.Amiel, J., Attie, T., Jan, D., Pelet, A., Edery, P., Bidaud, C., Lacombe, D.,
Tam, P., Simeoni, J., Flori, E., Nihoulfekete, C., Munnich, A., and Lyonnet, S.
(1996) Heterozygous endothelin receptor-b (EDNRB) mutations in isolated
hirschsprung disease. Hum. Mol. Genet. 5, 355–357.
116.Kusafuka, T., Wang, Y. P., and Puri, P. (1996) Novel mutations of the
endothelin-b receptor gene in isolated patients with Hirschsprungs-disease.
Hum. Mol. Genet. 5, 347–349.
117.Auricchio, A., Casari, G., Staiano, A., and Ballabio, A. (1996) Endothelin-b
receptor mutations in patients with isolated Hirschsprung disease from a
non-inbred population. Hum. Mol. Genet. 5, 351–354.
118.Attie, T., Till, M., Pelet, A., Amiel, J., Edery, P., Boutrand, L., Munnich, A.,
and Lyonnet, S. (1995) Mutation of the endothelin-receptor-b gene in
Waardenburg–Hirschsprung-disease. Hum. Mol. Genet. 4, 2407–2409.
119.Baynash, A. G., Hosoda, K., Giaid, A., Richardson, J. A., Emoto, N.,
Hammer, R. E., and Yanagisawa, M. (1994) Interaction of endothelin-3 with
endothelin-b receptor is essential for development of epidermal melanocytes
and enteric neurons. Cell 79, 1277–1285.
120.Edery, P., Attie, T., Amiel, J., Pelet, A., Eng, C., Hofstra, R. M. W., Martelli,
H., Bidaud, C., Munnich, A., and Lyonnet, S. (1996) Mutation of the
endothelin-3 gene in the Waardenburg–Hirschsprung disease (Shah–
Waardenburg syndrome). Nature Genet. 12, 442–444.
121.Hofstra, R. M. W., Osinga, J., Tan-Sindhunata, G., Wu, Y., Kamsteeg, E.-J.,
Stulp, R. P., van Ravenswaaij-Arts, C., Majoor-Krakauer, D., Angrist, M.,
Chakravarti, A., Meijers, C., and Buys, C. H. C. M. (1996) A homozygous
mutation in the endothelin-3 gene associated with a combined Waardenburg
type 2 and Hirschsprung phenotype (Shah–Waardenburg syndrome). Nature
Genet. 12, 445–447.
122.Bolk, S., Angrist, M., Xie, J., Yanagisawa, M., Silvestri, J. M., Weesemayer,
D. E., and Chakravarti, A. (1996) Endothelin-3 frameshift mutation in
congenital central hypoventilation syndrome. Nature Genet. 13, 395–396.