Download Genetics, genomics and gene discovery in the

# 2002 Oxford University Press
Human Molecular Genetics, 2002, Vol. 11, No. 10
1229–1240
Genetics, genomics and gene discovery in the
auditory system
Cynthia C. Morton*
Departments of Obstetrics, Gynecology, and Reproductive Biology and Pathology, Brigham and Women’s Hospital
and Harvard Medical School, Boston, MA, USA
Received April 5, 2002; Accepted April 10, 2002
INTRODUCTION
It has long been recognized that heredity plays a major role in
hearing impairment. Despite the fact that understanding the
genetic basis of hearing loss has fascinated human and medical
geneticists for decades, only within the past few years have the
genes and molecular mechanisms underlying deafness begun to
be discovered. In part, this results from various obstacles to
investigation of the auditory system including: inaccessibility
of the sensory end organ for hearing, the cochlea, within the
dense temporal bone; length of time to direct pathologic
observation of the deaf ear due to an otherwise normal lifespan
of individuals with hearing loss; unparalleled genetic heterogeneity; and assortative mating. The history of the genetics of
deafness has had a sordid past of blatant discrimination of the
deaf (1), and there is mistrust about genetics among some
members of the deaf population. Nevertheless, the past few
years have witnessed an explosion of discoveries that are
providing fundamental insight into the biology of hearing.
The frequency of hearing loss is estimated at one per
thousand newborns and half of all cases are attributed to
genetic causes. In addition to being a common etiology of
congenital deafness, mutations in genes are responsible for
progressive hearing loss, and no doubt will be found to play an
important role in progressive hearing loss with ageing
(presbycusis). Environmental etiologies of hearing loss are
likely to represent a declining proportion of cases as better
therapies for bacterial and viral infections (e.g. vaccines) are
implemented, acoustic trauma in the workplace is recognized
and prevented, and ototoxic drugs (e.g. aminoglycosides) are
avoided in genetically susceptible individuals.
GENETICS OF DEAFNESS
The study of the genetics of deafness is unique among inherited
disorders for several reasons and illustrates well various
concepts in human genetics. Notably, there is incomparable
genetic heterogeneity with over 90% of matings among the
deaf resulting in all hearing offspring. This reflects matings
among the deaf with mutations in different genes as well as
matings of couples in which one individual is deaf due to a
genetic mechanism and the other due to an environmental
etiology. Matings among the deaf are well recognized and, with
the exception of assortative mating for stature, may represent
one of the most common genetic traits on which an altered
mating structure occurs in human populations. Furthermore,
the hearing offspring of deaf couples who themselves can be
native signers are more likely than random members of the
population to have a partner who is deaf due to a shared
language and culture. Both genetic heterogeneity and assortative mating confound gene discovery using traditional methods
of genetic linkage analysis.
*To whom correspondence should be addressed at: Department of Pathology, Brigham and Women’s Hospital, 75 Francis Street, Boston, MA 02115, USA. Tel: 617
732 7980; Fax: 617 738 6996; Email: [email protected]
Downloaded from http://hmg.oxfordjournals.org/ at Pennsylvania State University on February 23, 2013
The sounds of silence have forever been broken as genetics and genomics approaches in human and model
organisms have provided a powerful and rapid entry into gene discovery in the auditory system. An
understanding of the complexities and beauty of the biological process of hearing itself is unfolding as genes
underlying hereditary hearing impairment are identified. Genes involved in modifying hearing are also being
found, and will be critical to a full comprehension of genotype–phenotype relationships. Investigations in the
auditory system will provide important insight into how the nervous system decodes molecular information.
Deafness represents a common sensory disorder that can interfere dramatically in the acquisition of speech
and language in children, and in the quality of life for a growing aged population. As newborn screening for
hearing impairment is being implemented in many birth hospitals, the prospects for precise clinical
diagnosis, appropriate genetic counseling and proper medical management for auditory disorders has never
been at a more exciting crossroad.
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Human Molecular Genetics, 2002, Vol. 11, No. 10
Table 1. Gene discovery in the auditory system
No.
Gene
1
ATP6B1
2
3
BSND
CDH23
CLDN14
COCH
COL1A2
COL2A1
COL4A3
COL4A4
COL4A5
COL11A1
COL11A2
13
14
15
16
DDP
DFNA5
DIAPH1
DSPP
17
barttin
cadherin 23
Syndromic or
nonsyndromic
hearing loss
Disorders
Reference
2cen–q13
SHL
(76)
1p32.3
10q21–q22
SHL
NSHL þ SHL
Distal renal tubular acidosis
associated with sensorineural
deafness
Bartter syndrome
Usher syndrome type 1D
(USH1D)
Usher syndrome type 1D
(USH1D) þ DFNB12
DFNB29
DFNA9
Osteogenesis imperfecta
Stickler syndrome (STL1)
Alport syndrome
Alport syndrome
Alport syndrome
Stickler syndrome (STL2)
Stickler syndrome (STL3)
DFNA13
Mohr-Tranebjaerg syndrome
DFNA5
DFNA1
Dentinogenesis imperfecta 1
(DGI1), DFNA39
Waardenburg–Shah syndrome
(WS4)
Waardenburg–Shah syndrome
(WS4)
Branchio-oto-renal syndrome
DFNA10
Autosomal recessive deafness
DFNB1
DFNA3
DFNA2
Autosomal recessive deafness
DFNA3
Jervell and Lange–Nielsen
syndrome (JLNS2)
DFNA2
Jervell and Lange-Nielsen
syndrome (JLNS1)
Waardenburg syndrome type II
(WS2)
Tietz syndrome
May–Hegglin and Fechtner
syndromes
DFNA17
DFNA22
Usher syndrome type 1B
(USH1B)
DFNA11
DFNB2
Atypical Usher syndrome
DFNB3
Norrie disease
DFNB9
Waardenburg syndrome type I
(WS1)
Waardenburg syndrome types
I þ III (WS1 þ WS3)
Craniofacial dysmorphism,
hand abnormalities, profound
sensorineural deafness
(CDHS)
Usher syndrome type 1F
(USH1F)
DFN3
21q22
14q12–q13
7q22.1
12q13.1–q13.2
2q36–q37
2q36–q37
Xq22
1p21
6p21.3
NSHL
NSHL
SHL
SHL
SHL
SHL
SHL
SHL
NSHL þ SHL
diaphanous
dentin sialophosphoprotein
Xq22
7p15
5q31
4q21.3
SHL
NSHL
NSHL
SHL
EDN3
endothelin 3
20q13.2–q13.3
SHL
18
EDNRB
endothelin receptor B
13q22
SHL
19
20
21
22
EYA1
EYA4
GJA1
GJB2
connexin 43
connexin 26
8q13.3
6q22–q23
6q21–q23.2
13q12
SHL
NSHL
NSHL
NSHL
23
GJB3
connexin 31
1p34
NSHL
24
25
GJB6
KCNE1
connexin 30
13q12
21q22.1–q22.2
NSHL
SHL
26
27
KCNQ4
KVLQT1
1p34
11p15.5
NSHL
SHL
28
MITF
3p12.3–p14.1
SHL
29
MYH9
myosin heavy chain 9
22q13
NSHL þ SHL
30
31
MYO6
MYO7A
myosin 6
myosin 7A
6q13
11q12.3–q21
NSHL
NSHL þ SHL
32
33
34
35
MYO15A
NDP
OTOF
PAX3
36
PCDH15
37
POU3F4
claudin 14
cochlin
collagen type
collagen type
collagen type
collagen type
collagen type
collagen type
collagen type
Map position
1 a2
2 a1
4 a3
4 a4
4 a5
11 a1
11 a2
myosin 15A
norrin
otoferlin
protocadherin 15
17p11.2
Xp11.3
2p22–p23
2q35
NSHL
SHL
NSHL
SHL
10q21–q22
SHL
Xq21.1
NSHL
(77)
(10)
(11)
(78)
(22)
(79)
(80)
(23)
(23)
(20)
(81)
(82)
(83)
(16)
(19)
(84)
(85)
(86)
(87)
(88)
(89)
(67)
(24)
(25)
(26)
(90)
(66)
(91,92)
(93)
(94)
(28)
(95)
(96)
(97)
(49)
(7)
(6)
(8,9)
(98)
(99)
(14,100)
(29)
(27)
(101)
(102)
(103,104)
(105)
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4
5
6
7
8
9
10
11
12
Protein or RNA
Human Molecular Genetics, 2002, Vol. 11, No. 10
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Table 1. (Continued)
POU4F3
PMP22
12S rRNA
SLC19A2
peripheral myelin
ribosomal RNA
5q31
17p11.2
mitochondrial
1q23.3
NSHL
SHL
NSHL
SHL
42
SLC26A4
pendrin
7q31; 7q21–q34
NSHL þ SHL
43
44
45
46
47
SOX9
SOX10
STRC
TCOF1
TECTA
stereocilin
treacle
alpha tectorin
17q24.3–q25.1
22q13
15q21–q22
5q32–q33.1
11q22–q24
SHL
SHL
NSHL
SHL
NSHL
48
TMC1
9q13–q21
NSHL
49
50
51
TMPRSS3
tRNA-glu
tRNA-leu
transfer RNA
transfer RNA
21q22.3
mitochondrial
mitochondrial
NSHL
SHL
SHL
52
tRNA-lys
transfer RNA
mitochondrial
SHL
53
tRNA-ser
transfer RNA
mitochondrial
SHL
54
tRNA-ser(UNC)
transfer RNA
mitochondrial
NSHL þ SHL
55
USH1C
harmonin
11p15.1
SHL
56
57
58
USH2A
USH3
WFS1
usherin
1q41
3q21–q25
4p16
SHL
SHL
SHL
NSHL
wolframin
Hundreds of syndromic forms of deafness have been
described (2–4) and the underlying genetic mutation identified
for many of the more common forms, but only 30% of genetic
cases are estimated to be part of a heritable syndrome. Thus,
the vast majority of genetic deafness is designated as
nonsyndromic and to date over 65 loci have been mapped.
Nonsyndromic hearing impairment is categorized further by
mode of inheritance: approximately 77% of cases are
autosomal recessive; 22% autosomal dominant; 1% X-linked;
and < 1% due to mitochondrial inheritance (5). Dominant loci
are designated with the prefix ‘DFNA’, recessive loci ‘DFNB’,
X-linked loci ‘DFN’ and modifying loci with ‘DFNM’.
Generally, patients with autosomal recessive hearing impairment have prelingual and congenital deafness and patients with
autosomal dominant hearing impairment have postlingual and
progressive hearing impairment. This observation may be
explained by the complete absence of functional protein in
recessive disorders, while in autosomal dominant disorders,
dominant mutations may be consistent with initial function and
subsequent hearing impairment due to a cumulative, degenerative process. A recent tally of nonsyndromic hearing loss
disorders reveals 32 autosomal dominant, 27 autosomal
recessive, and 4 X-linked forms (4). It remains to be shown
whether each of these loci will correspond to a unique gene. In
fact, various deafness disorders have been found already to be
DFNA15
Charcot–Marie–Tooth disease
Sensorineural deafness
Thiamine-responsive megaloblastic
anemia with diabetes mellitus
and deafness
Pendred syndrome (PDS)
DFNB4
Campomelic dysplasia
Waardenburg–Shah syndrome (WS4)
DFNB16
Treacher Collins syndrome
DFNA8, DFNA12
DFNB21
DFNA36
DFNB7/B11
DFNB8, DFNB10
Diabetes and deafness
Myopathy, encephalopathy, lactic
acidosis and stroke-like episodes (MELAS)
Diabetes mellitis and deafness
Myoclonic epilepsy and ragged-red fiber
disease (MERRF)
Retinitis pigmentosum and progressive
sensorineural hearing loss
Sensorineural deafness
Progressive myoclonic epilepsy, ataxia
and hearing loss
Palmoplantar keratoderma and deafness
Usher syndrome type 1C (USH1C)
Usher syndrome type 2A (USH2A)
Usher syndrome type 3 (USH3)
Wolfram syndrome
DFNA6/A14
DFNA38
(69)
(106)
(74)
(107,108)
(17)
(109)
(110)
(111)
(31)
(15)
(21)
(112)
(12)
(113)
(114)
(115)
(116)
(117)
(118)
(119)
(120)
(121)
(30)
(122)
(18)
(123)
(124,125)
(126)
(127)
the result of the same genetic etiology (e.g. DFNA8 and A12;
DFNA6, A14 and A38). In addition, at least 58 auditory genes
have been identified: 16 for autosomal dominant and 11 for
autosomal recessive loci, and 1 for an X-linked locus; 6 mitochondrial genes and at least 38 genes for syndromic hearing
loss have also been discovered (n.b. some genes cause multiple
forms of deafness) (Table 1). Although this magnitude of progress is remarkable and significant advances have been made, it
is clear that many more genes for hearing await detection.
Mutations within the same gene have been found to result in
a variety of clinical phenotypes with different modes of
inheritance. For example, mutations in MYO7A are pathogenetic in the autosomal recessive deafness and blindness
disorder Usher syndrome type 1B (USH1B), and in two
nonsyndromic hearing disorders, DFNB2 and DFNA11,
displaying autosomal recessive and dominant segregation,
respectively. It has been suggested that the mutation in
DFNA11, a 9 bp deletion in the coiled-coil domain of MYO7A
which is involved in dimerization, could have a dominant
negative effect (6) as compared to splicing and missense
mutations observed in recessive USH1B and DFNB2 (7–9).
Another example of phenotypic heterogeneity also involving
Usher syndrome is seen in mutations in CDH23 detected in
USH1D and DFNB12 (10,11). Mutations in PDS cause
Pendred syndrome and nonsyndromic autosomal recessive
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38
39
40
41
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Human Molecular Genetics, 2002, Vol. 11, No. 10
hearing loss, DFNB4. Similarly, mutations in WFS1 cause
Wolfram syndrome and also account for an autosomal
dominant nonsyndromic deafness, DFNA6/A14/A38. Most
recently, DFNA36 and DFNB7/B11 were determined to be the
result of mutations in TMC1 (12).
GENOMIC APPROACHES TO GENE DISCOVERY
IN THE AUDITORY SYSTEM
A complementary method to genetic linkage analysis for gene
identification is one that utilizes tissue or organ-specific cDNA
libraries to provide candidate genes (32–34). A transcript map
of the inner ear provides a ready source of positional candidate
genes for mutation screens in gene discovery efforts. To this
end, cochlear cDNA libraries constructed from human (35,36)
and mouse (37) have provided precious biological tools for
gene discovery in the mammalian cochlea. A cDNA library
from an analogous organ in chicken, the basilar papillae, has
also been of great value (38). Almost 15 000 human (Morton
fetal cochlear cDNA library) and 1600 mouse (Soares mouse
NMIE cDNA library) inner ear ESTs are currently available in
GenBank and the sequences of an additional 9000 mouse ESTs
will soon be deposited there. ESTs derived from two
sequencing projects from human cochlear cDNA clones
(39,40) have elucidated thousands of potential positional
candidate genes for hearing disorders (41) in addition to
providing a snapshot of gene expression in the 16–22 week
gestational age fetal cochlea. BLAST analysis of 8153 human
ESTs revealed that about 50% (n ¼ 4040) had sequence
similarity to a total of 1449 known human genes. The most
abundantly expressed gene was COL1A2, and two other
collagens, COL3A1 and COL1A1, were among the most highly
represented transcripts. In total, 10 different collagen genes
were present in the cochlear ESTs. Forty-three human
homologs of nonhuman mammalian genes were also identified,
and among them are ESTs for membrane proteins, extracellular
proteins and trafficking proteins. Of the remaining 4055 ESTs,
Table 2. Web resources for genetic and genomic studies of the auditory system
Web page name
Summary of contents
URL
Connexin-deafness homepage
Corey lab
Information on connexin mutations
Microarray expression data from
mouse inner ear
Resources for families, clinicians and
researchers
Results from a large scale mouse screening
program
Syndromic and nonsyndromic disorders,
mitochondrial disorders, otosclerosis
Human cochlear ESTs summary and map
locations
Mouse mutants with various inner ear defects
www.iro.es/deafness/
www.mgh.harvard.edu/depts/
coreylab/index.html
hearing.harvard.edu
Harvard Medical School Center
for Hereditary Deafness
Hereditary hearing impairment in mice
Hereditary hearing loss homepage
Morton hearing research group
MRC Institute of Hearing Research inner
ear mutant table
MRC Institute of Hearing Research inner ear
developmental gene expression table
National Institute on Deafness and Other
Communication Disorders
OMIM
Otobase
Tour de l’oreille, Université Montpellier
Univ. of WI Dept. of Neurophysiology—Hearing
and Balance
Washington Univ. inner ear protein database
Developmental gene expression in the
inner ear in a variety of species
Research from the Laboratory of Molecular
Genetics and other resources
Human heritable disorders
Repository of candidate genes for inner ear
disorders in human, mouse and zebrafish
Anatomy, physiology and pathophysiology
of the auditory system
Educational and research resources
Catalog of biochemical characterization
of tissues and fluids of the inner ear
www.jax.org/research/hhim
www.uia.ac.be/dnalab/hhh/
hearing.bwh.harvard.edu
www.ihr.mrc.ac.uk/hereditary/
MutantsTable.shtml
www.ihr.mrc.ac.uk/hereditary/
genetable/index.shtml
www.nidcd.nih.gov/
www.ncbi.nlm.nih.gov/entrez/
query.fcgi?db ¼ OMIM
Hudspeth-sgi.rockefeller.edu
www.iurc.montp.inserm.fr/cric/
audition/english/start.htm
www.neurophys.wisc.edu/h%26b
oto.wustl.edu/thc/innerear2d.htm
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Traditional methods for mapping disease genes, such as genetic
linkage analysis, have a less than totally optimal use in gene
discovery efforts for hearing disorders, mainly because of the
complex genetic nature of deafness. Successful use of genetic
linkage for mapping hearing disorders, especially for autosomal
recessive nonsyndromic loci, has been restricted largely to
consanguineous kindreds or populations in which there has been
limited immigration. Even in families in which a heritable
hearing disorder is successfully mapped, there is often an
insufficient number of recombination events to narrow a
chromosomal interval, resulting in a candidate region consisting
of megabases of genomic DNA. Positional cloning has been
productive for a modest number of human deafness genes
including NDP (13,14), TCOF1 (15), DDP (16), SLC26A4 (17),
USH2A (18) and DFNA5 (19). Positional candidate genes from
human (e.g. COL4A5 (20), TECTA (21), COCH (22), COL4A
and 4A4 (23), GJB2 (24,25), GJB3 (26)) and mouse (e.g. PAX3
(27), MITF (28), OTOF (29), USH1C (30), STRC (31)) among
others have been the primary method for gene identification.
Organ and tissue-specific methods for auditory candidate
genes
Human Molecular Genetics, 2002, Vol. 11, No. 10
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Table 3. Mouse hearing loss mutants and their human homologs
Gene
Human disorder(s)
References
Ames waltzer (av)
Beethoven (Bth) and deafness (dn)
chondrodysplasia(cho)
Col1a1 transgene disruption
Col11a2 targeted null
Col4a3 targeted null
Disproportionate micromelia (Dmm)
and mutant transgenes
Dominant megacolon (Dom)
dominant spotting (W)
Eya1bor and targeted null
Fgfr3 targeted null
Gata targeted null
Pcdh15
Tmc1
Col11a1
Col1a1
Col11a2
Col4a3
Col2a1
Usher syndrome type 1F (USH1F)
DFNA36, DFNB7/B11
Stickler syndrome type 2 (STL2)
Osteogenesis imperfecta (OI)
Stickler syndrome type 3 (STL3), DFNA13
Alport syndrome
Stickler syndrome type 1 (STL1)
(103,104,128)
(12,50)
(81,129,130)
(131–134)
(82,83)
(23,135)
(80,136,137)
Sox10
Kit
Eya1
Fgfr3
Gata3
(111,138,139)
(140–142)
(88,143,144)
(145,146)
(147,148)
Kcne1 targeted null and Kcne1pkr
Kcnq1 targeted null
lethal spotting (ls)
microphthalmia (mi)
Kcne1
Kcnq1
Edn3
Mitf
Ndph targeted null
Pax2 targeted null
piebald (s)
Pou3f4 targeted null and sex-linked fidget (slf)
Pou4f3 targeted null and dreidel (ddl)
quivering (qv)
shaker-1 (sh1)
Ndph
Pax2
Ednrb
Pou3f4
Pou4f3
Spnb4
Myo7a
shaker-2 (sh2)
Slc26a4 targeted null
Snell’s waltzer (sv)
splotch (Sp)
Myo15a
Slc26a4
Myo6
Pax3
Tecta targeted null
Thrd targeted null
tremble (Tr)
waltzer (v)
Tecta
Thrb
Pmp22
Cdh23
Waardenburg–Shah syndrome (WS4)
Piebald trait (PBT)
Branchio-oto-renal syndrome (BOR)
Craniosynostosis
Hypoparathyroidism, sensorineural deafness
and renal dysplasia syndrome (HDR)
Jervell and Lange–Nielsen syndrome (JLNS2)
Jervell and Lange–Nielsen syndrome (JLNS1)
Waardenburg–Shah syndrome (WS4)
Waardenburg syndrome type 2 (WS2),
Tietz syndrome
Norrie disease (ND)
Renal-coloboma syndrome
Waardenburg–Shah syndrome (WS4)
DFN3
DFNA15
Charcot-Marie-Tooth disease type 4F (CMT4F)
Usher syndrome type 1B (USH1B), DFNB2,
DFNA11, atypical Usher syndrome
DFNB3
Pendred syndrome (PDS), DFNB4
DFNA22
Waardenburg syndromes types 1 and 3 (WS1, WS3),
Craniofacial dysmorphism, hand abnormalities,
profound sensorineural deafness (CDHS)
DFNA8/A12, DFNB21
Thyroid hormone resistance
Charcot-Marie-Tooth disease type 1A (CMT1A)
Usher syndrome type 1D (USH1D), DFNB12
3277 had sequence similarity to other ESTs representing 2266
unique clusters; 778 categorized into 700 clusters had no
sequence similarity to known genes or ESTs and can be
considered to be ‘cochlear-specific’. Identification of additional
known genes, ESTs and ‘cochlear-specific’ ESTs provides new
candidate genes for both syndromic and nonsyndromic deafness disorders. A variety of web resources have been developed
for genetic and genomic studies of the auditory system that
facilitate candidate gene approaches and are listed in Table 2.
In addition to sequence-based approaches, gene expression
chips provide an important means to explore the repertoire of
cochlear messages in the normal and diseased state. Data from
gene chip assays are available on the web for normal mouse
cochlea for ages P2 and P32 (42).
Several preferentially expressed cochlear genes, namely
COCH (43) and OTOR (44,45), have been identified from the
human fetal cochlear cDNA library; COCH was further shown
to be responsible for a sensorineural deafness and vestibular
disorder, DFNA9 (22). Various genes have been identified from
a similar approach using mouse inner ear transcripts and
include Otog (37), Ocn95 (46), Ush1c (30), Fdp (mouse
homolog of OTOR) (47) and Strc (31); the human homolog of
(91,92,149,150)
(94,151,152)
(86,153)
(28,95,154,155)
(13,14,156)
(157,158)
(87,159)
(105, 160–162)
(69,163,164)
(165)
(7,9,98,166,167)
(99,168)
(17,109,169)
(48,49)
(27,101,102,170,171)
(21,112,172)
(173,174)
(106,175,176)
(10,11,177)
Ush1c was found to underlie mutations in USH1C and of Strc
to be etiologic in DFNB16.
Mouse models for discovery of hearing genes
Identification of mouse models of specific forms of deafness is
of great interest as the mouse is clearly the model organism of
choice for the study of hearing loss in humans. The mouse
cochlea is highly similar in structure to that of the human.
Studies of mouse mutants from fetal to adult ages makes
possible investigation into the pathology at developmental time
points simply not possible in humans. Of particular relevance to
understanding the pathobiology and underlying molecular
mechanisms of genetic mutations is the ability to evaluate
early developmental stages in mouse mutants because hair cell
defects may result from degenerative processes secondary to a
primary abnormality in another cell type. Although there has
been tremendous progress in identifying genes underlying
deafness, there are still relatively few mouse models (Table 3).
In some instances, identification of the mouse mutation has
greatly preceded detection of the human disorder (48,49),
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Mouse mutant
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Human Molecular Genetics, 2002, Vol. 11, No. 10
GENE DISCOVERY IN THE AUDITORY SYSTEM:
THE PATH TO IMPROVED DIAGNOSIS AND
CLINICAL CARE
Inspection of the genes identified in hearing disorders and those
among the gene lists from the EST sequencing projects reveals
a great diversity of transcripts, perhaps not surprising due to the
large variety of cells and complexity of the inner ear. The
finding of a large percentage of cochlear ESTs not identified in
any other tissue may indicate the existence of genes that are
unique to the cochlea. Certainly, the great degree of genetic
heterogeneity reflected in the many different syndromes
involving hearing loss and mapped loci is indicative of a large
number of genes orchestrating the hearing process. Grouping
the genes discovered to be etiologic in deafness disorders into
functional categories begins the process of understanding their
role in hearing. Knowledge of the pathways in which many of
these genes function will be an exciting journey in hearing
science; no doubt pathways exist that are not yet imagined.
Another important aspect of gene discovery for deafness
disorders is that it makes possible the development of
diagnostic tests and accurate genetic counseling. Appropriate
medical management and therapeutic options may be based on
an understanding of the specific disorder.
Gap junction proteins: the connexins
Prominent among the group of genes are those encoding gap
junctions. A somewhat surprising finding in the field has been
the prevalence of mutations in a single gene encoding the gapjunction protein connexin 26, GJB2, accounting for up to 50%
of all cases of autosomal recessive prelingual deafness in tested
populations (54–65). Connexin 26 gap junctions are believed to
play a critical role in the recycling of potassium ions from their
entry into hair cells during sensory transduction from the
endolymph through to the stria vascularis, where other
potassium channels pump potassium back into the endolymph.
The gap junction itself, the connexon, is formed from six
monomers of connexin and forms a pore between cells by
binding with a connexon on an adjacent cell. Several recurrent
mutations have been found in GJB2 (e.g. 35delG, 167delT, and
235delC), some with ethnic predilections. In addition to the
recurrent mutations, the gene is small (681 bp) making it
especially amenable for genetic testing. Screening for mutations in GJB2 has already emerged as the cornerstone of
genetic testing for hearing loss and has been incorporated in
some centers into the clinical work-up of infants who fail
newborn hearing tests. The connexin-deafness homepage provides information on connexin mutations in deafness (Table 2).
Besides GJB2, genes for other gap junction proteins have been
found to be associated with hearing loss including GJB3 (26),
GJB6 (66) and GJA1 (67). A curious finding in genetic testing
of the deaf for GJB2 has been the frequent observation of
heterozygosity for a mutation. Various explanations have been
proposed including the possibility that the deafness was due to
another gene or that there was a mutation in a non-coding
region of GJB2 not evaluated in the test. Recent identification
of a 342 kb deletion in the GJB6 gene (D(GJB6–D13S1830)) as
the second most frequent mutation causing prelingual deafness
in the Spanish population may provide the sought after answer
in many cases (68). GJB6 maps within the same chromosomal
region as GJB2, and these recently published data suggest that
mutations in the DFNB1 locus can result in a monogenic or
digenic pattern of inheritance. Of note, the typical mutationdetection assays commonly in use may miss such large
deletions.
Genes for maintenance of hair cell function
Another group of genes of intense interest are those required
for survival of sensory hair cells. The POU domain
transcription factor gene POU4F3 is required for terminal
differentiation and maintenance of inner hair cells and an 8 bp
deletion in the POU homeodomain results in progressive
hearing loss in DFNA15 (69). Studies of such genes may result
in valuable insight into the molecular triggers for hair cell
degeneration. Loss of hair cells is presumed to be a
fundamental cause of progressive age-related hearing loss
(presbycusis) and an understanding of this degenerative process
might provide the basis for therapeutic intervention. The recent
finding of the transmembrane cochlear-expressed gene TMC1
uncovers a common cause of nonsyndromic recessive deafness
in Pakistan and India at the DFNB7/B11 locus on chromosome
9 in bands q13–q21; mutations in TMC1 account for the
deafness phenotype in 5.4 3.0% of 230 families screened
(12). Cloning of TMC1 resulted from an interesting genomicsbased approach that first involved identification of a predicted
gene (subsequently designated TMC2) on chromosome 20 with
sequence similarity to query sequences in a tBLASTx analysis
of a BAC from the linked genetic interval. TMC1 mutations
were also found to be etiologic in DFNA36 (12) and in the
mouse mutants deafness (dn) (12) and Beethoven (Bth) (50). It
is predicted that TMC1 protein may mediate an ion-transport or
channel function required for the normal function of hair cells.
Downloaded from http://hmg.oxfordjournals.org/ at Pennsylvania State University on February 23, 2013
whereas in other cases discovery of the genetic basis for
deafness has occurred concurrently (12,50). Positional cloning
of deafness genes in the mouse is facilitated by the ability to
breed large numbers of mice with the same mutation to narrow
the interval for study. A large screen of inbred mouse strains by
ABR threshold analyses at The Jackson Laboratory is currently
underway, and likely to identify mutants that will lead to
discovery of new genes and modifying genes for deafness (51).
In addition, large numbers of new mouse mutants for
investigating mammalian gene function including deafness
are being generated rapidly through ENU mutagenesis (52).
This chemical mutagenesis program also makes possible genedriven approaches to mouse mutants and using this approach,
two missense and one stop mutation were recently identified in
Gjb2, the most common cause of nonsyndromic deafness in the
human population (53). Besides the spontaneous deaf mouse
mutants and those generated from mutagenesis programs, a
number of gene targeting experiments have been performed
following identification of the human gene, and have provided
valuable mouse mutants for investigation. As the human and
mouse DNA sequencing projects are finished, the mouse–
human synteny maps will also become better defined and it will
become increasingly easier to locate potential mouse mutants
for mapped human deafness disorders.
Human Molecular Genetics, 2002, Vol. 11, No. 10
The recessive dn mutant displays no auditory response and has
secondary hair cell degeneration and the dominant Bth mutant
appears to have normally functioning hair cells prior to
degeneration.
Modifier genes
Mitochondrial genes
A variety of mitochondrial disorders have been found to involve
hearing loss, perhaps reflecting the highly metabolic state of
the hearing process (73). Of particular interest has been the
A1555!G mutation in 12S rRNA that is recognized as the
most frequent cause of aminoglycoside-induced deafness and
as the etiology of a nonsyndromic deafness (74). In a recent
study a nearly identical degree of mitochondrial dysfunction
was observed in enucleated lymphoblastoid cells derived from
both symptomatic and asymptomatic individuals from the same
kindred (75) supporting the possibility of a nuclear gene in
modifying the effect of the mutation.
Investigations in hereditary deafness have revealed many
lessons in genetics, foremost among them a sensory system
with profound genotypic and phenotypic heterogeneity. Despite
the recent tremendous successes in the genetics of deafness, our
knowledge remains woefully incomplete. An astonishing
number of deafness loci have been mapped in humans and
mice, yet the genetic basis of many disorders remains unknown.
Genomic approaches using a combination of methods of
positional cloning, candidate genes and mouse models continue
to yield new and novel genes providing valuable insight into the
molecular basis of the process of hearing.
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