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(Investigative Ophthalmology and Visual Science. 2002;43:3153-3159.)
© 2002 by The Association for Research in Vision and Ophthalmology, Inc.

Mapping of A Gene Responsible for Cataract Formation and Its Modifier in the UPL Rat

Satoshi Yamashita1, Kayo Furumoto2, Asako Nobukiyo3, Masashi Kamohara1, Toshikazu Ushijima1 and Toshinori Furukawa3

1 From the Carcinogenesis Division, National Cancer Center Research Institute, Tokyo, Japan; 2 Shimizu Laboratory Supplies Company, Ltd., Kyoto, Japan; and the 3 Research Facilities for Laboratory Animal Science, Hiroshima University, School of Medicine, Hiroshima, Japan.


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
PURPOSE. The Upjohn Pharmaceuticals Limited (UPL) rat is a unique model for cataracts, which are inherited as an autosomal semidominant trait and expressed as early-onset (E-type) cataracts in homozygotes and as late-onset (L-type) cataracts in heterozygotes. In this study, a gene and its modifier, which are responsible for formation of cataract, were mapped.

METHODS. Fifty-five BN x (BN x UPL)F1 backcross rats and 133 BN x UPL intercross rats were produced. The cataracts present in the rats at eye opening were diagnosed as E-type. Cataracts that developed after eye opening were diagnosed as L-type, and the ages when complete opacity in the lens was observed were used as a quantitative trait to map a gene that modifies the development of mature cataracts. Linkage analysis was performed using 64 arbitrarily primed-representational difference analysis (AP-RDA) markers and 74 microsatellite markers.

RESULTS. A gene responsible for the formation of cataract was mapped to the vicinity of D2Rat134 on rat chromosome (chr) 2. A candidate gene, connexin 50 (Cx50/Gja8), had a C-to-T transition at codon 340 that is predicted to result in a nonconservative substitution of arginine by tryptophan. Recombination in the Cx50 genotype and formation of cataract was not observed. By quantitative trait loci analysis, a gene that modified the age of the development of mature cataract was mapped on rat chr 5.

CONCLUSIONS. A candidate gene for formation of cataracts in UPL rats was mapped to rat chr 2, and the Cx50 gene was a strong candidate. In addition, a potential modifier gene was mapped on chr 5. Future cloning of these genes will provide good targets for new therapies that can delay the progression of cataracts.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
Congenital cataracts are one of the major causes of induced blindness in children. Inherited cataracts account for up to half of congenital cataracts, and the most frequent mode of inheritance is autosomal dominant.1 To clarify the responsible genes for inherited cataract, animal models are useful, because one or a limited number of genes are involved in one specific animal model, and those genes can be mapped easily. In the mouse, more than 70 genes responsible for inherited cataract have been mapped, and at least 14 of them are of autosomal dominant inheritance.2 3 4 5 Some of the genes have already been identified.4 5 However, the detailed mechanism of the development of cataract remains unclear. Furthermore, there are only a few reports of the mapping of genes responsible for cataract in the rat.6

The UPL rat was founded as a mutant with cataracts in a colony of Crj:SD (SD) rats at Tsukuba Research Laboratory, Upjohn Pharmaceuticals Limited, (Ibaraki, Japan) in 1989.7 Genetic analysis of the mutant showed that a single gene was semidominantly involved in the development of cataract.7 Homozygotes of UPL rats displayed early-onset (E-type) cataract, which manifested as lens opacification before eye opening at 14 days of age7 and was often accompanied by microphthalmos and/or buphthalmos.7 The differentiation of lens epithelial cells is known to be impaired in E-type UPL cataract.8 Heterozygotes of UPL rats displayed late-onset (L-type) cataract that started to appear at 2 to 4 weeks of age and developed into complete opacity of the lenses in both eyes (mature cataract) at 7 to 8 weeks of age.7 9 The initial change in the L-type cataract is hydration of the lens fibers at the anterior suture, and the hydration then spreads through the entire cortex of the lens.9 In both E-type and L-type cataracts, proteolyzed {alpha}-crystallin cannot be detected initially, but can be detected as the cataracts progress.10 The UPL rat shows no abnormalities in its lifespan, growth, and blood tests for hematology and chemistry and is considered a good model for congenital cataract, congenital microphthalmos, abnormal lens development (E-type), and various human cataracts (L-type). In spite of these, there is little knowledge of the gene responsible for the formation of cataract in the UPL rat.

In this study, we mapped the gene responsible for cataract in the UPL rat by linkage analysis. By using the ages when complete opacity in the lens was observed, we were also able to map a modifier gene in the mature cataract. By synteny analysis, a strong candidate gene for formation of cataract, rat Cx50, was identified, and its mutation in the UPL rat was demonstrated.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Animals and Assessment of Cataracts
The UPL rat strain was maintained as a closed colony at research facilities for laboratory animal science at Hiroshima University School of Medicine. Male homozygotes of UPL rats and female Brown-Norway/Sea (BN) rats were mated to produce F1 progeny. F1 rats were backcrossed to female BN rats to produce backcross rats, and were intercrossed to F2 intercross rats. None of the BN rats had cataract.

The lenses of rats were examined once a week with a direct ophthalmoscope and a slit lamp microscope, to observe any opacity in the lens. When rats had lens opacity at eye opening at the age of 2 weeks, E-type cataracts were diagnosed. When any lens opacity was observed by the age of 6 months, the rats were placed on further observation until complete opacity of the lens was observed in both eyes (mature cataracts). L-type cataracts were diagnosed in these rats, and the ages when mature cataracts developed were recorded. Rats that did not show any changes in the lenses by the age of 6 months were classified as noncataract. All animals were treated in accordance with the Guidelines for Animal Use of Hiroshima University, School of Medicine and the ARVO Statement for the Use of Animals in Ophthalmic and Vision Research.

Genomic DNA was extracted from rat livers or tails by an automated DNA extractor (Genextractor TA-100; Takara Shuzo, Kyoto, Japan).

Genotyping Using AP-RDA Markers and Microsatellite Markers
Genotyping with the AP-RDA markers (http://www.ncc.go.jp/research/rat-genome/, provided in the public domain by the National Cancer Center Research Institute, Tokyo, Japan), which is suitable for genotyping of a large number of animals, was performed as reported previously.11 12 An AP amplicon of each rat was prepared by AP-PCR with an appropriate primer. The PCR solution was mixed with denaturing solution and dot blotted onto a nylon membrane (HyBond-N+; Amersham Biosciences, Uppsala, Sweden). Each of the AP-RDA markers was labeled using a random prime module (Gene Images; Amersham Biosciences), and hybridization/detection was performed with a chemiluminescence detection kit (Gene Images CDP-Star detection module; Amersham Biosciences).

Genotyping with microsatellite markers was performed as reported previously.13 PCR was performed with appropriate primers purchased from Research Genetics, Inc. (Huntsville, AL) using 20 ng of genomic DNA as a template. Electrophoresis of the PCR products was performed on a 4% agarose (NuSieve; Cambrex Corp., East Rutherford, NJ) gel in 0.5x TBE buffer. A rat coat color marker, Tyr, was genotyped by the presence of albino coat color. The 139 markers used in this study (64 AP-RDA markers, 74 microsatellite markers, and 1 coat color marker) are summarized in Table 1 . The genotypes UPL/UPL, UPL/BN, and BN/BN are denoted U/U, U/B, and B/B, respectively.


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  		Table 1. The Polymorphic Markers Used in the Study

 
Linkage Analysis
Linkage maps were drawn on computer (Mapmaker/EXP; provided in the public domain by the Whitehead Institute for Biomedical Research, Cambridge, MA, and available at http://www.wi.mit.edu).14 For linkage analysis with formation of cataract, linkage disequilibrium of the genotypes in rats was examined at each locus by the {chi}2 test. The ages of mature cataracts were log transformed and quantitative trait loci (QTL) analysis was performed using the gene-mapping software.15

Sequencing of the Rat Cx50 Gene and Analysis of Its Polymorphism
The coding sequences of rat Cx50 was amplified from genomic DNA in three fragments using three sets of forward (F) and reverse (R) primers based on the mouse Cx50 sequence (GenBank accession AF304357; GenBank is provided in the public domain by the National Center for Biotechnology Information, Bethesda, MD, and is available at http://www.ncbi.nlm.nih.gov/genbank): 1F, 5'-GAGTTGCACTGTGGCCAATT-3', 1R, 5'-CCACGATGAAGCCCACCTCA-3'; 2F, 5'-AGAAGTTCCGGCTGG-3', 2R, 5'-CTCCCACTTCCGGTTCCACA-3'; and 3F, 5'-CACTATTTCCCTTTGACG-3', 3R, 5'-CTAACAGCAGTTGGGATAGA-3'. Direct sequencing was performed with a kit and automated DNA sequencer (BigDye Terminator kit and ABI310 DNA sequencer; Applied Biosystems, Foster City, CA).

For PCR and restriction fragment length polymorphism (RFLP) analysis of Cx50, PCR was performed using primer 4F, 5'-GCCAAGCCTTTTAGTCAG-3' and 4R, 5'-TCACTAGGACAGTGGGTTTA-3', with an annealing temperature of 55°C. The PCR product was restricted with 5 U AciI (New England BioLabs, Beverly, MA) and run in a 2.0% agarose gel.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Phenotypes in Backcross and Intercross Progeny
Segregation of the phenotypes in the F1, backcross, and intercross rats is summarized in Table 2 . L-type cataracts developed in all 22 (BN x UPL)F1 rats. L-type cataracts were observed in 33 BN x (BN x UPL)F1 backcross rats; 22 of 55 of these rats were not affected. L-type cataracts developed in 65 (BN x UPL)F2 intercross rats and E-type in 32; 36 of 133 rats were not affected. This 1:2:1 segregation ratio confirmed that cataracts were inherited as a semidominant monogenic trait.7


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  		Table 2. Segregation of Phenotype of Rats Analyzed in the Study

 
To explore the possible presence of a gene that modifies the development of mature cataracts, the ages when mature cataracts were observed (termed the ages of mature cataracts) were examined. The average age of mature cataracts was 80 days in (BN x UPL)F1 progeny, which were heterozygous in the responsible locus and had the BN/SD background, 91 days in the intercross rat with L-type cataracts, and 104 days in the backcross rats with L-type cataracts. These average ages of mature cataracts were significantly higher (P < 0.001; Student’s t-test) than the ages of cataracts in the original heterozygous UPL rats (50 days),9 which were heterozygous in the responsible locus and had the SD/SD background. This suggests that BN rats have a modifier gene(s) that delays the development of mature cataract. There was no sex difference (P = 0.72 in F1 rats, P = 0.57 in the backcross rats, and P = 0.59 in the intercross rats; Student’s t-test).

Mapping of a Gene Responsible for Cataract
Backcross rats were genotyped with 42 AP-RDA markers and 71 microsatellite markers, with an average interval of 16.2 centimorgans (cM). F2 intercross rats were genotyped with 49 AP-RDA markers, 74 microsatellite markers, and one coat color marker with an average interval of 15.0 cM.

By linkage analysis with formation of cataract in the backcross rats (Table 3) and the intercross rats (Table 3 ; Fig. 1A ), a strong linkage was observed on rat chromosome (chr) 2 around D2Rat134. At D2Rat134, all the intercross rats with E-type cataract had the U/U genotype, and all the intercross rats with L-type cataract had the U/B genotype. However, rat 307, in which lens opacity was not observed at the age of 214 days, had the U/B genotype at D2Rat134 and the B/B genotype at D2Rat186, showing that the responsible gene was in a region between D2Rat134 and D2Rat186 (Fig. 1B) . The gene responsible for formation of cataract was named Uca (UPL rat cataract). A comparative map among rat, mouse, and human chromosomes16 showed that the region between D2Rat134 and D2Rat118, the vicinity of Uca, corresponded to mouse chr 3 (30–56 cM) and human chrs 3q25-q26, 1q21-q23, and 1p21-p13. In addition to Uca, weak and additional linkages were observed, only in the backcross rats, on chrs 4 and 16 ({chi}2 = 8.6, P = 0.003 and {chi}2 = 5.5, P = 0.02, respectively, Table 3 ).


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  		Table 3. Linkage Analysis with Cataract Formation in the Backcross and Intercross Rats

 


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  		Figure 1. Fine mapping of the Uca gene in the intercross rats. A total of 133 (BN x UPL) F2 intercross rats were genotyped, and analysis of linkage with formation of cataract was performed. (A) Distribution of haplotypes for chr 2 in rats with E-type cataract, those with L-type cataract, and those without cataract. ({blacksquare}) U/U, () U/B, and ({square}) B/B genotype at each locus. (B) Localization of the Uca gene on rat chr 2 was narrowed down to an interval between D2Rat134 and D2Rat186 by the genotypes of rats 227 and 307, in which lens opacity was not observed by the ages of 210 and 214 days, respectively. Genetic distances are shown in centimorgans (cM) to the left of the chromosome.

 
QTL Analysis of the Ages of Mature Cataracts
QTL analysis of the ages of mature cataracts was performed in the intercross rats with L-type cataract (n = 65). The average age of mature cataract was 90.7 ± 24.6 (average ± SD) days, and ranged from 61 to 212 days (Table 2) . A QTL was observed between D5Rat33 and D5Rat93 on rat chr 5 with a peak LOD (logarithm of odds) score of 5.0 (Fig. 2A) , which was considered significant according to a criterion of Lander and Kruglyak.17 The QTL was named Ucad1 (UPL rat cataract delay 1). When the rats were classified by their genotypes at D5Rat93, the average ages of mature cataracts were 78.7 ± 10.7, 87.6 ± 15.4, and 111.4 ± 36.4 days in the rats with the U/U, U/B, and B/B genotypes, respectively (Fig. 2B) . The average age of the rats with the B/B genotype was significantly delayed compared with that of the rats with the U/U genotype and those with the U/B genotype (P = 0.001 and 0.031, respectively; Scheffé test). This effect of the Ucad1 gene explained 32.4% of the variance in the ages of mature cataracts. No other significant or suggestive linkages were observed in the other chromosomes, however. A comparative map16 showed that rat chr 5 between D5Rat33 and D5Rat93 corresponded to mouse chr 4 (57–65 cM) and human chr 1p36-p33. The Ucad1 gene did not affect whether cataract formed (Table 3) .



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  		Figure 2. QTL analysis of the ages of mature cataracts. (A) A QTL for the development of mature cataract around D5Rat93. The LOD scores obtained in interval mapping of QTL with the ages of mature cataracts are displayed. Dotted line: significant level of linkage in the intercross rats (P = 5.2 x 10-5, LOD score = 4.3). (B) Effect of Ucap1 on the ages of mature cataracts. The intercross rats were classified by their genotype at D5Rat93, and the number of rats with mature cataracts were classified by age range at which cataracts matured. Rats with the B/B genotype showed significantly delayed development of mature cataract.

 
Sequence and Genotype of Cx50
The CX50 (GJA8) gene, a mutation of which is known to cause cataract in humans,18 19 was found to be located in human 1q21, close to the Uca gene. To analyze its mutations in UPL rats, the coding region of the rat Cx50 gene was determined (GenBank accession number: AB078344). Rat Cx50 had a coding sequence of 1323 bp, the same length as mouse Cx50. The homology of the rat gene with the human CX50 and mouse Cx50 genes was 87% and 95%, respectively.

PCR and direct sequencing were performed for the entire coding sequences in homozygotes of UPL and BN rats. A base substitution of T for C in codon 340, which is predicted to result in substitution of arginine by tryptophan (R340W), was observed in UPL rats (Fig. 3A) . The amino acid R340 was in the carboxyl terminus and was conserved between the rat and mouse (Fig. 3B) . For rapid detection of this mutation, PCR-RFLP analysis was developed based on the fact that a recognition site of the AciI enzyme (5'-GCGG-3') was disrupted by the mutation (Fig. 3C) . Using this PCR-RFLP marker, the 55 backcross and 133 intercross rats were genotyped. All 32 rats with E-type cataracts were homozygotes for this mutation, all 98 rats with L-type cataracts were heterozygotes, and all 58 rats without cataracts did not have the mutation (Fig. 3D) . The Cx50 gene was mapped as D2Rat134-(0.3 cM)-Cx50-(3.5 cM)-D2Rat186. Eleven strains of rats that do not have hereditary cataracts—ACI, BN, BUF, F344, Donryu, LEA, LEC, Lewis, SHRSP, Wistar Furth, and WKAH—had no mutation at R340 (data not shown).



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  		Figure 3. Genotyping of the Cx50 gene and its linkage with formation of cataract. (A) A mutation found in the Cx50 gene of the UPL rat. (B) Comparison of the sequences around the mutation among the human, mouse, and rat. (C) Detection of the Cx50 mutation by PCR-RFLP analysis. PCR was performed spanning a polymorphic AciI site, and the product was digested with AciI. E-type UPL rats (lane 1), which had the SD background, displayed a band for an undigested product only, and BN rats (lane 2) displayed a band for a digested product only. (BN x UPL)F1 rats (lane 3), which had the BN/SD background and L-type cataracts, displayed both bands, showing that they were heterozygous for the mutation. The original heterozygous UPL rats (lane 4), which had the SD/SD background and L-type cataracts, also displayed both bands, showing that the mutation was not inherent in SD rats. M, 100-bp DNA ladder. (D) Genotypes of the Cx50 gene. There was no recombination between its genotype and formation of cataract. Symbols in (D) are as described in Figure 1A .

 

   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
In this study, we mapped the Uca gene, which determines formation of cataract in the UPL rat, to a 3.6-cM interval of rat chr 2. Candidate genes, which were found in syntenic human chromosomal regions—chrs 3q25-q26, 1q21-q23, and 1p21-p13—included CX50, collagen type XI {alpha}-1 (COL11A1)20 and beaded filament structural protein 2 (BFSP2).21 22 CX50 is abundantly expressed in the lens and oligomerizes with other connexins to form a connexon, one half of the gap junction channel that forms gap junctions.23 Missense mutations in codon 88 of CX50, located in the second membrane-spanning domain, are known to cause autosomal dominant "zonular pulverulent" type cataract in humans.18 The Cx50 mutations in codons 22 and 47 also have been suggested to cause cataract in mice,24 25 and Cx50-null mice exhibit microphthalmia and nuclear cataract.26 27 Based on these findings, we analyzed mutations of Cx50 in UPL rats and found the R340W mutation. There was no recombination between the mutation status and formation of cataract in the 55 backcross and 133 intercross rats.

The R340W mutation was expected to result in a nonconservative amino acid change in the carboxyl terminus of Cx50. Although the carboxyl terminus is variable among different connexin members,28 it is conserved among animal species (Fig. 3B) . The carboxyl terminus contains phosphorylation sites for different kinases, and it is considered to be important for Cx50-specific functions.28 The nonconservative amino acid change in the carboxyl terminus could affect some of these functions of Cx50. Moreover, the R340W mutation was never observed in 11 rat strains that do not have hereditary cataracts. Therefore, Cx50 is a strong candidate for the Uca gene. A rescue experiment using a wild-type Cx50 transgene would be valuable in drawing a final conclusion.

QTL analysis using the ages of mature cataracts was performed in the intercross rats with L-type cataracts, all of which had the heterozygous R340W mutation in Cx50. By this QTL analysis, the Ucad1 gene was mapped to rat chr 5, and its BN genotype significantly delayed the development of mature cataract. This region corresponded to human chr 1p36-p33, and several candidate genes were found in the vicinity of this region. A cluster of four connexin genes, CX31, CX37, CX31.1, and CX30.3, was found in human 1p35.1. Forkhead transcription factor, FOXE3, the mutations of which are associated with anterior segment ocular dysgenesis and cataract,29 was found in human 1p32. Mutation of CX31 is known to cause deafness, but the functions of the other genes are unknown. When a rat had the B/B genotype in the Ucad1 locus, the development of cataract was delayed with the formation of L-type cataract, but formation occurred. Recent reports have shown that some of the functional defects caused by Cx50 deletion could be restored by other connexins, such as Cx46, but that some other defects could not be restored.27 30 Assuming that the Cx50 mutation is the Uca mutation, the probability that the Ucad1 gene is also one of the connexin genes is high. An incomplete Cx50 product in rats with heterozygous mutations could be compensated for by the contribution of another connexin to form connexon in the lens. The compensation effect is thought to be better performed by the BN-type than the UPL (SD)-type, but either type has enough activity to suspend the formation of cataract.

The Ucad1 gene explained 32.4% of the variance in the ages of mature cataracts, and its effect seems quite strong considering the large variance of the ages, even in inbred strains. The total effect of the BN background on the delay of formation of cataract can be assessed by comparing the original heterozygous UPL rat, which has the heterozygous Uca gene in the SD background, and a congenic strain that has the heterozygous Uca gene in the BN background. We are constructing such a congenic strain. Once the total effect of the BN background is assessed, the contribution of the Ucad1 gene can also be assessed accurately.

In this study, we successfully mapped a gene responsible for formation of cataract to chr 2 and a gene that modifies its development to rat chr 5. Cx50 is a strong candidate for the Uca gene. The molecular characterization of the Ucad1 gene will offer a good target for drug development that will delay the progression of cataract.


   Acknowledgements
 
The authors thank Takashi Kuramoto for helpful comments.


   Footnotes
 
Supported by a Grant-in-Aid for Human Genome and Tissue Regeneration from the Ministry of Health, Labor and Welfare.

Submitted for publication February 5, 2002; revised May 17, 2002; accepted June 12, 2002.

Commercial relationships policy: N.

The publication costs of this article were defrayed in part by page charge payment. This article must therefore be marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact.

Corresponding author: Toshikazu Ushijima, Carcinogenesis Divison, National Cancer Center Research Institute, 1-1 Tsukiji 5-chome, Chuo-ku, Tokyo 104-0045, Japan; tushijim{at}ncc.go.jp.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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