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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. 2502 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 Downloaded From: http://arvojournals.org/pdfaccess.ashx?url=/data/journals/iovs/933420/ on 06/17/2017 Mapping of the Coc Locus 2503 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 Downloaded From: http://arvojournals.org/pdfaccess.ashx?url=/data/journals/iovs/933420/ on 06/17/2017 2504 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 Downloaded From: http://arvojournals.org/pdfaccess.ashx?url=/data/journals/iovs/933420/ on 06/17/2017 2505 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- Downloaded From: http://arvojournals.org/pdfaccess.ashx?url=/data/journals/iovs/933420/ on 06/17/2017 2506 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. References 1. Spencer WH. Lens. In: Ophthalmic Pathology. 4th ed. Philadelphia: WB Saunders; 1996:372-437. 2. Lund AM, Eiberg H, Rosenberg T, Warburg M. Cataract; linkage relations: Clinical and genetic heterogeneity. Clin Genet. 1992;41:65-69. 3. Bateman JB, Spence MA, Marazita ML, Sparkes RS. Genetic linkage analysis of autosomal dominant congenital cataracts. AmJ Ophthalmol. 1986; 101:218-225. 4. Barrett DJ, Sparkes RS, Gorin MB, et al. Genetic linkage analysis of autosomal dominant congenital cataracts with lens specific DNA probes and polymorphic phenotypic markers. Ophthalmology. 1988;95:538-544. 5. Eiberg H, Lund AM, Warburg M, Rosenberg T. Assignment of congenital cataract Volkmann type (CCV) to chromosome Ip36. Hum Genet. 1995;96:33-38. 6. Renwick JH, Lavvler SD. Probable linkage between a congenital cataract locus and the Duffy blood group locus. Ann Hum Genet. 1963; 27:67-84. 7. Rogaev El, Rogaeva EA, Ko rovai tseva GI, e t al. Li n kage of polymorphic congenital cataract to the 7-crystallin gene locus on human chromosome 2q33-35. Hum Mol Genet. 1996;6:699-703. 8. Marner E, Rosenberg T, Eiberg H. Autosomal dominant congenital cataract: Morphology and genetic mapping. Ada Ophthalmol. 1989;67:151-158. 9. Berry V, Ionides ACW, Moore AT, Plant C, Bhattacharya SS, Shiels A. A locus for autosomal dominant anterior polar cataract on chromosome I7p. Hum Mol Genet. 1996;5:415-419. 10. Padma T, Ayyagari R, MurtyJS, et al. Autosomal dominant zonular cataract with sutural opacities localized to chromosome 17qll-12. Am J Hum Genet. 1995; 57:840-845. 11. Armitage MM, Kivlin JD, Ferrell RE. 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Zhou E, Grimes P, Favor J, et al. Genetic mapping of a mouse ocular malformation locus, Tcm, on chromosome 4. Mamm Genome. 1997;8:178-181. Downloaded From: http://arvojournals.org/pdfaccess.ashx?url=/data/journals/iovs/933420/ on 06/17/2017