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Mapping of the Autosomal Dominant Cataract Mutation
(Coc) on Mouse Chromosome 16
DuskaJ. Sidjanin,* Patricia A. Grimes,* Walter Pretsch,^ Angelika Neuhduser-Klaus,f
Jack Favor, f and Dwight E. Stambolian*
Purpose. To characterize the mouse cataract mutation Coc.
Methods. Coc is an X-radiation-induced autosomal dominant cataract mutation maintained
on a murine C3H inbred strain. The affected heterozygotes were outcrossed to C57BL/6,
and (C3H Coc/+ X C57BL/6) mice that were Coc/+ were then backcrossed to C57BL/6 to
generate a panel of 103 progeny for mapping. For linkage analysis, microsatellites from each
autosome were selected. The maximum distance between markers was 30 centimorgans (cM).
Results. The initial genome-wide screen of 14 backcrossed progeny indicated that die Coc
locus resides on chromosome 16. Further mapping with additional markers from chromosome
16 for all 103 backcrossed progeny positioned Coc between markers D16MU134 and D16MU63.
This region is syntenic to human chromosome 3.
Conclusions. Mapping of the Coc locus to mouse chromosome 16 provides the positional
information necessary to identify the candidate gene responsible for the Coc phenotype. The
molecular characterization of the gene disrupted in the Coc mutation will provide insight into
the mechanisms involved in cataract formation. Invest Ophthalmol Vis Sci. 1997; 38:25022507.
Vjongenital cataracts are estimated to cause 10% to
38% of all childhood blindness. 1 Of the inherited
forms in humans, autosomal dominant cataracts are
the most common. 1 Mapping of human cataract loci
has been limited by genetic heterogeneity, 2 " 4 making
it difficult to clone a human cataract locus. Presently,
eight loci for autosomal dominant cataracts have been
mapped. 5 " 12 However, only two loci have been associated with a gene mutation. The Coppock-like cataract
is associated with novel activation of the yE-crystallin
pseudogene, 13 whereas mutations at the PAX6 locus
were identified in patients with Peters' anomaly.14
To circumvent barriers of direct linkage studies
in humans, the available mouse models have been
From the *Department of Ophthalmology and Scheie Eye Institute, University of
Pennsylvania School of Medicine, Philadelphia; and the f Institute of Mammalian
Genetics, GSF—National Research Center for Environment and Health, Neuherberg,
Germany.
Supported in part by the National Institutes of Health, Bethesda, Maryland (grants
F32 EY06715 and R01 EY10321), and by a postdoctoral fellowship from the John
Ijickie Research Fund of the Fight for Sight Research Division of Pi event Blindness
America, Schamburg, Illinois (DJS).
Submitted for publication Febntaiy 19, 1997; revised June 18, 1997; accepted June
20, 1997.
Proprietary interests category: N.
Reprint requests: Diuighl Stambolian, University of Pennsylvania, IHGT, RoomSOS, 422 Curie Boulevard, Philadelphia PA 19104-6069.
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used to identify genes responsible for cataract development. One advantage of using mouse mutants is the
easy breeding of large litters that provide statistically
significant data. A second advantage is that the mouse
genome is well characterized with many mouse-to-human homologies. Comparative genetic maps between
human and mouse provide a method for predicting
the location of human disease genes on the basis of
their location in the mouse genome. 15 Many mouse
eye mutations have been identified and are available
for study.16"18 Table 1 lists the autosomal dominant
mouse mutations associated with cataracts that have
been mapped. 16 " 18
The Coc mutation analyzed in this study was recovered in the offspring of a 5.1 + 5.1 Gy X-irradiated
male. 19 The mutant (originally designated R-322) was
outcrossed to wild type C3H mice to confirm the genetic nature of the lens opacity,20 and subsequent genetic analysis demonstrated autosomal dominant inheritance. The homozygotes were viable and heterozygotes and homozygotes expressed a similar phenotype
of coralliform flecks in the lens nucleus. 20 Allelism
tests against 15 independent dominant cataract mutations indicated that Coc is a distinct entity.21 As an
Investigative Ophthalmology & Visual Science, November 1997, Vol. 38, No. 12
Copyright © Association for Research in Vision and Ophthalmology
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Mapping of the Coc Locus
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TABLE l.
Mapped Autosomal Dominant Eye Mutations Expressing
Cataracts
Mutation
Chromosome
Phenotype
Cat2
Cat4a
Ccw
Coc
Lop4
1
8
4
16
C
CO
C
C
C
Mip
10
5
16
19
2
Npp
opj
Pax2
Pax6
Phyl
Tern
To2
To3
2
5
4
10
7
Reference
Everett et al2fi
Favor et al33
Kerscher et alS4
Present study
West and Fisher15
Shiels and Bassnett3fi
Everett et al26
Everett et al26
Favor et alS7
Hill et alS8
Chambers and Russell19
Zhou et al40
Everett et al2Cl
Kerscher et al34
C
C
c
CO
CO
c
c
c
CO
C = cataract; CO = cataract and other ocular abnormalities.
initial step in the isolation and characterization of the
utes at 1700g, and pellets were washed with 70% ethaCoc gene, we mapped Coc relative to simple sequence nol, air dried, and resuspended in water.
length polymorphisms (SSLPs).
To identify the chromosomal region that contains
the Coc locus rapidly, we selected microsatellite markers for each chromosome approximately 30 centiMETHODS
morgans (cM) apart. We used microsatellites, in which
the difference in fragment sizes between C3H and
Mapping
C57BL/6 strains varied from 5 bp to 60 bp. As exThe C3H Coc/+ animals were outcrossed to C57BL/
pected, each progeny carried a C57BL/6 allele, and
6 and Coc/+ outcross progeny were backcrossed to
only some carried the C3H allele (Fig. 1).
C57BL/6. The progeny were examined at weaning (3
Primer pairs for the SSLPs were obtained from
weeks of age) for cataracts. Examination was done by
Research
Genetics (Huntsville, AL). For initial linkage
slit lamp microscope, after mydriasis with 1 % atropine.
analysis,
we
performed polymerase chain reactions on
Carrier heterozygotes express nuclear coralliform
14
backcross
progeny with the following 51 microsatel
flecks, which is easily diagnosed by our examination
lite
markers:
D1MU14, D1MU231, D1MU181,
procedures. In a total of 103 backcross progeny, 56
D2MU241,
D2MU226,
D2MU190, D3MU73, D3MU151,
were diagnosed with cataracts. The backcross progeny
D3MU258,
D4MU193,
D4MU12, D4MU27, D5MU205,
and their parents were killed with CO2) and liver tissue
D5MU138,
D6MU201,
D6MU213, D6MU1,
D5MU99,
was removed and frozen at — 70°C.
D7MU191,
D7MU229,
D8MU4,
D8MU113,
D7MU40,
DNA was extracted from liver tissue following a
22
D8MU31,
D9MU75,
D9MU129,
D9MU182,
D10MU95,
D
standard protocol. Briefly, 100 mg of frozen liver was
10MH38,
D10MH180,
D11MU82,
D11MU258,
crushed to a fine powder and suspended in 1.2 ml of
digestion buffer containing 100 mM NaCl, 10 mM D11MU38, D12MU83, D12MU5, D12MU46, D13MU218,
D13MU48, D13MU24, D14MU78, D14MH102,
Tris-Cl (pH 8), 25 mM ethylenediaminetetraacetic
D15MU156, D15MU111, D16MU114, D16MU154,
acid (pH 8), 0.5% sodium dodecyl sulfate (all chemicals were obtained from Sigma Chemical Co., St.
Louis, MO), and 0.1 mg/ml proteinase K (Boeh12 3
4 5 6 7 8 9 10 11 12 1314
ringer-Mannheim, Indianapolis, IN). Samples were in203 —
cubated at 37°C overnight. Samples were extracted
with equal volumes of phenol (Boehringer-Mann187 - »
heim), chloroform (Fisher Biotech, Fair Lawn, NJ),
and isoamyl alcohol (Sigma Chemical) and were centrifuged for 10 minutes at l700g. Aqueous layers were
FIGURE l. Amplified DNA from 14 progeny with DJ6MU63
transferred to new tubes and to each was added a
marker. The C57BL/6 allele is 203 bp, whereas the C3H
one-half volume of 7.5 M ammonium acetate (Sigma
allele is 187 bp. Each allele is represented on the autoradioChemical) and two volumes of 100% ethanol (Farmco,
graph by several bands. Interpretation is unambiguous for
Brookfield, CT). Samples were centrifuged for 2 minalleles that differ in size by more than 1 bp.
r
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Investigative Ophthalmology & Visual Science, November 1997, Vol. 38, No. 12
D17MU142, D17MU135, D18MU120, D18MU40,
D19MU16, D19MU11. The polymerase chain reactions
were done according to the protocol from Research
Genetics. Briefly, the forward polymerase chain reaction primer for each marker was end-labeled with
[32P]adenosine triphosphate using T4 polynucleotide
kinase (New England Biolabs, Beverly, MA). The forward end-labeled and reverse primers (each 0.1139
//M) were used in a 10-//1 amplification reaction with
20 ng of genomic mouse DNA, 1.5 mM MgCl2, 0.2
mM dNTP, 1 X polymerase chain reaction buffer, and
0.25 U of Taq polymerase (all reagents were obtained
from Life Technologies, Gaithersburg, MD). Reactions were amplified in a PTC-100 Programmable
Thermal Controller (MJ Research, Watertown, MA)
using the following protocol: initial denaturation at
94°C for 3 minutes, followed by 25 cycles of 94°C for
1 minute, 55°C for 2 minutes, and 72°C for 2 minutes.
The polymerase chain reaction products were diluted
twofold with loading buffer containing 100% formamide, denatured for 2 minutes at 80°C, and cooled
on ice for 5 minutes. The samples were electrophoresed on 6% denaturing polyacrylamide gels for 3
hours at 20 V/cm. Gels were dried and exposed to xray film for 16 hours at —80°C.
Linkage data were analyzed with Map Manager
version 2.6.23 Chromosomal location was determined
by minimizing the number of multiple crossovers.
All animals were treated in accordance with the
ARVO Statement for the Use of Animals in Ophthalmic and Vision Research.
Histology
Two litters were generated from a cross of heterozygotes (Coc/+ X Coc/ + ) and were killed at embryonic
days (E) 16 and 17. A total of 11 embiyos were fixed
in Carnoy's solution for 24 hours and were transferred
to 70% ethanol. The heads were embedded in Historesin (Leica Instruments, Heidelberg, Germany) and
sectioned coronally at 6 fim. Serial sections through
the eyes were stained with toluidine blue for light microscope examination.
RESULTS
Mapping
For all markers except those on chromosome 16, approximately 50% of the 14 backcross progeny were
recombinants. The results showed tight linkage of the
Coc locus to the chromosome 16 markers; no crossovers were detected with D16MU154, and one crossover was detected with D16MU114 of 14 progeny
tested. To refine the position of the Coc locus, we
selected nine additional markers from chromosome
16 {D16MU12, D16MU101, D16MU91, D16MU139,
D16Hltl5t
D16Hltl6S
DlSMltlOl
DieMitlO3
D16Xltl3i
D16Mlt38
Coc
D16U1H3
Dl SKlt S3
DlSHlt91
DlSMltl39
DIStSltlli
45
• • • D •
35
1
4
3
3
1
1
2
O
1.0
-D16Xltl54
-Diemties
6.8
•D16NltlO3,DlSMltl34
2.9
1.0
1.0
2.9
2.9
-Coc,D16Mlt38,D16Mltl2
-D16Mlt63
•D16Mit91
-DlSMltl39
-D16Uitllt
FIGURE 2.
Chromosomal mapping of the Coc locus. The segregation patterns of Coc and 11 markers in 103 backcross
progeny are shown at the top. Each vertical column represents the haplotype identified in the backcross progeny that
was inherited from the F] parent. • = C3H allele; • =
C57BL/6 allele. The number of offspring inheriting each
type of chromosome is listed at the bottom of each column.
The map at the bottom is a partial chromosome 16 linkage
map, showing the location of Coc in relation to linked markers. Recombination distances between loci (in centimorgans; cM) are shown to the left of the chromosome.
D16MM34, D16Mitl65, D16MU38, D16MU63, and
D16MU103) and analyzed all 103 backcross progeny.
No recombinants were detected among 103 progeny
with markers D16MU12 and D16MU38, suggesting that
they were close to the Coc locus. The most likely order
of Coc and the surrounding markers on chromosome
16 is D16Mitl54-D16Mitl65-D16MU101-{D16Mitl03, D
16Mitl34)-{D16Mitl2, Coc, D16Mit38)-D16Mit63D16Mit91-D16Mitl39-D16Mitll4. The observed chromosome 16 haplotypes and a linkage map of the Coc
locus are shown in Figure 2.
Histology
Coc/ -V and Coc/Coc mice express fleck opacities in the
lens nucleus that are detectable under the slit lamp
microscope. Histologic evidence of this phenotype was
identified in E16 and E17 embryos. Nine of 11 examined embryos derived from Coc/ + X Coc/ -V matings
showed abnormal lens structure and were presumed
to be Coc/+ or Coc/Coc genotypes. The remaining two
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Mapping of the Coc Locus
FIGURE 3. Lens fiber lesions associated with the Coc mutation
in an embryo (embryonic day 16). (A) Typical area of lens
fiber disintegration {arrows) is evident in the primary nucleus. Lens epithelium, equatorial region of differentiating
fibers and secondary fibers are normal. (B) Higher magnification of the abnormal area seen in A). An amorphous pool
of acidophilic material is surrounded by fibers with extremely dense or coarsely reticular cytoplasm [arrows). Intensely basophilic droplets [arrowheads) are scattered
throughout the area of fiber breakdown. Toluidine blue;
magnification bars = 100 /xm.
embryos, demonstrating no histologic defects, were
presumed to be + / + . In the abnormal embryos, one
to several small areas of lens fiber degeneration were
seen in the primary nucleus (Fig. 3). The disrupted
fibers surrounded lakes of amorphous acidophilic material. Small basophilic droplets, most likely the residue of degenerated fiber cell nuclei, were commonly
present. The lens epithelium, lens bow region, and
layer of secondary fibers were normal in all of these
embryos, as were other ocular structures.
DISCUSSION
Successful gene mapping depends on the density and
informativeness of markers on the genetic map. The
availability of a large series of mouse polymorphic
probes makes genetic mapping of mouse loci possible.
Simple sequence repeats occur frequently in the mammalian genome and are a good source of markers.24
The current mouse genetic map consists of 6580
SSLPs spanning approximately 1300 cM, with an average spacing of 1.1 cM.25
Using SSLPs, we mapped the Coc cataract mutation to the region of Dl6M.it!2 and D16MU38, which
is ~26 cM distal to the centromere on chromosome
16. This map location eliminated the possibility that
the Coc mutation may be allelic to the only autosomal
dominant cataract mutation shown to be on chromosome 16 Opj, which is ~ 6 cM from the centromere. 26
In the region of the Coc locus, the Mouse Genome
Database (MGD) l5 lists several genes. However, on the
basis of the phenotype of the known mutant alleles,
none of these genes seem likely candidates for Coc.
The mammalian hairy and enhancer of split-1 (Hesl)
maps at the same position as Coc. Mice homozygous
for the Hesl mutation exhibit severe neurulation de-
fects and die during gestation or just after birth.27
In E15.5 and E17.5 embryos of Hesl null mice the
development of neural retina, lens and cornea is severely disturbed.28 Because of the more severe phenotype, the Hesl gene does not seem to be a suitable
candidate for the Coc mutation.
The alkaptonuria (aim) mutation is the mouse
genetic model for human alkaptonuria, an autosomal
recessive metabolic disease characterized by a very
high urinary excretion of homogentisic acid.2'1 Affected mice show high levels of urinary homogentisic
acid without other physical signs. The aim locus shows
tight linkage to D16MU4, which maps at the same position as D16MU12. Thus, aku could be a candidate gene
for the Coc/Coc mutation on the basis of gene location.
However, one visible feature of the aku mutant is the
darkening of the cage bedding, caused by high urinary
concentration of homogentisic acid in urine, which
polymerizes into dark pigment. No such darkening of
the cage bedding has been observed in the Coc/Coc
mutation, suggesting that aku is not the candidate
gene.
The Ly7 antigen locus also maps in the region
~26 cM from the centromere on chromosome 16.
The Ly7 antigen specificity is present on lymphocytes
and is absent from liver, kidney, brain, and red blood
cells.30 Specifically, Ly7 antigen is expressed in very
low amounts on thymocytes, but is readily detectable
on more mature T and B lymphocytes, with the greatest expression on B cells.30 Even though lens tissue
has not been tested for the presence of Ly 7 antigen,
it is very likely that Ly7 antigen is lymphocyte-specific
and hence, an unlikely candidate for the Coc mutation.
The ckr, chakragati mouse, was created by injecting a DNA fragment containing the mouse Ren2
gene into (C57BL/10Ros X C3H/HeRos) fertilized
eggs.31 The insertion interrupted a gene on chromosome 16 in the region of the Coc locus. The ckr mouse
shows circling behavior that is nor. present in the Coc/
Coc mutant, making it an unlikely candidate gene for
the Coc locus.
The Coc locus lies in a region with conserved synteny to human chromosome 3. The yS-crystallin gene
has been assigned to human chromosome 3 based
on a panel of hamster-human somatic cell hybrids.32
Even though yS-crystallin is an attractive candidate
gene for the Coc mutation, the exact location of yScrystallin on human chromosome 3 has not been determined, and it may not map in a syntenic region
with mouse chromosome 16.
If a candidate gene for the Coc mutation cannot
be identified among previously cloned genes, identification of the novel gene responsible for the Coc mutation will likely depend on future efforts in positional
cloning. For this purpose, more refined mapping of
the Coc locus will be necessary and will require devel-
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Investigative Ophthalmology & Visual Science, November 1997, Vol. 38, No. 12
opment of another backcross. The isolation and characterization of the mouse Coc gene will allow us to
isolate the homologous human gene.
neous anterior segment malformations including Peters' anomaly. Nat Genetics. 1994;6:168-73.
15. Peters J, Searle AG. Linkage and synteny homologies
in mouse and man. In: Lyon MF, Rastan S, Brown
Key Words
candidate genes, congenital cataracts, genetic locus, genetic
map, mouse cataracts
Acknowledgments
The authors thank Bianca Hildebrand and Irmgard Zaus
for conducting animal breeding studies and Brigitte Koeberlein for her assistance in embryo embedding and sectioning.
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