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A Novel Locus of Coralliform Cataract Mapped to Chromosome 2P24-Pter

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A Novel Locus of Coralliform Cataract Mapped to Chromosome 2P24-Pter J Hum Genet (2005) 50:305–310 DOI 10.1007/s10038-005-0251-y SHORT COMMUNICATION Linghan Gao Æ Wei Qin Æ Hao Cui Æ Guoyin Feng Ping Liu Æ Weiqi Gao Æ Lin Ma Æ Pu Li Æ Lin He Songbin Fu A novel locus of coralliform cataract mapped to chromosome 2p24-pter Received: 14 January 2005 / Accepted: 23 March 2005 / Published online: 3 June 2005 Ó The Japan Society of Human Genetics and Springer-Verlag 2005 Abstract Congenital cataract is a common major interval at a novel disease locus 2p24-pter between abnormality of the eye, which can result in significant D2S297 and D2S2268. No genes related to cataract in visual impairment or blindness in childhood. In this this region have been reported so far. work, we studied four generations of a Chinese family that exhibited autosomal dominant coralliform cataract Keywords Autosomal dominant congenital cataract but no other ocular or systemic abnormalities. Members (ADCC) Æ Coralliform cataract Æ Linkage analysis Æ of the family were firstly genotyped with microsatellite Genetic heterogeneity markers at loci associated with congenital cataract on the reported regions of chromosomes 1, 2, 3, 10, 11, 12, 13, 15, 16, 17, 20, 21, and 22, but negative LOD scores were obtained. Following exclusion of these loci, a Introduction genome-wide scan was performed, and significant evidence of linkage was obtained for marker D2S2211 Cataract refers to the loss of transparency in the lens of (Z = 2.69, h = 0.00). In multipoint analysis, a maxi- the eyes. During the critical phrase of vision forming, mum LOD score 4.87 (h = 0.00) was reached between opacities of the neonatal lens can cause blurring of markers D2S2211 and D2S2164. Haplotype data indi- vision. Congenital cataract is a common major abnor- cated a coralliform cataract disease gene in a 26-cM mality of the eye, which can result in significant visual impairment or blindness in childhood, accounting for an estimated one-tenth of clinical childhood blindness Linghan Gao, Wei Qin, and Hao Cui contributed equally to this work. worldwide (Gilbert et al. 1993). The World Health Organization (WHO) has set itself the task, as a part of L. Gao Æ P. Li Æ S. Fu (&) its international program, to eliminate avoidable blind- Laboratory of Medical Genetics, Harbin Medical University, ness due to congenital cataract by 2020 (Thylefors 1998). 194 Xuefu Road, Harbin, 150086, P.R. China E-mail: [email protected] Congenital cataract shows a wide variety of pheno- Tel.: +86-451-86676560 typic and genotypic heterogeneity. The relationship be- Fax: +86-451-86632768 tween morphology and genetic etiology is not yet clear. W. Qin Æ G. Feng Æ L. He Morphological variations of congenital cataract are Bio-X Life Science Research Center, many and complex (Amaya et al. 2003), and no uni- Shanghai Jiao Tong University, 1954 Huashan Road, versal classification system has yet been adopted by Shanghai, 200030, P.R. China researchers worldwide. At present, congenital cataract W. Qin Æ G. Feng Æ L. He can be divided into several types according to their Institute for Nutritional Sciences, specific morphology based on location and appearance Shanghai Institute of Biological Sciences, of lens opacities. Such categories include anterior polar, Chinese Academy of Sciences, 319 Yueyang Road, Shanghai, 200031, P.R. China posterior polar, nuclear, lamellar (zonular), pulverulent, cerulean, total, cortical, polymorphic, sutural, aculei- H. Cui Æ P. Liu Æ W. Gao Æ L. Ma form, and coralliform, etc. (Amaya et al. 2003; Francis Eye Hospital of the First affiliated Hospital, Harbin medical University, 23 Youzheng Street, et al. 2000; Reddy et al. 2004). Approximately one- Harbin, 150001, P.R. China quarter to one-third of congenital cataract is hereditary. S. Fu Among the three types of Mendelian inheritance in Bio-pharmaceutical Key Laboratory of Heilongjiang Province, congenital cataract, autosomal dominant appears to be 194 Xuefu Road, Harbin, 150086, P.R. China the most significant. At least seventeen loci of autosomal 306 dominant congenital cataract (ADCC) have been map- molecular analysis and clinical investigation of the ped by linkage analysis on 13 human chromosomes. family. These loci are: 1p36 (Eiberg et al. 1995; Ionides et al. 1997), 1q21–q25 (Renwick and Lawler 1963), 2p12 (Khaliq et al. 2002), 2q33–q35 (Lubsen et al. 1987; Gene scan Rogaev et al. 1996), 3q21–q22 (Jakobs et al. 2000), 10q24–q25 (Semina et al. 1998), 11q22.3–q23.1 (Berry Blood samples were obtained, and genomic DNA was et al. 2001), 12q13 (Bateman et al. 2000), 13cen-q13 extracted from peripheral blood leukocytes using con- (Mackay et al. 1997), 15q21–q22 (Vanita et al. 2001), ventional methods. DNA samples were amplified with 16q22.1 (Eiberg et al. 1988), 17p (Berry et al. 1996), three-temperature touchdown PCR: 96°C for 12 min; 17q11.1-q12 (Padma et al. 1995), 17q24 (Armitage et al. followed by 14 cycles at 95°C for 30 s, 64°C for 1 min 1995), 20p12-q12 (Yamada et al. 2000), 21q22.3 (Litt (with a temperature decrease from 64°Cto57°Cby et al. 1998), and 22q11.2 (Hulsebos et al. 1995). 0.5°C per cycle), 72°C for 1.5 min; followed by 30 cycles Cataract-related proteins that play vital roles in the at 95°C for 30 s, 57°C for 1 min, and 72°C for 1.5 min; structure and function of the lens include crystallins, lens and a final extension at 72°C for 10 min, in a Gene Amp connexin (Cx 50 and Cx 46), major intrinsic protein PCR System 9700 (PE Applied Biosystems, USA). (MIP), cytoskeletal protein (CP49), and lens-develop- Standard PCR reaction was preformed in a 5-ll volume mental protein (PITX3). Crystalline genes are major containing 50 ng genomic DNA, 1 lM of each primer, candidates in relation to congenital cataract because of 300 lM dNTP, 10 mM Tris–HCl (pH8.3), 50 mM KCl, their abundant expression in the lens, and they can be 1.5 lM MgCl2, 3 U Hotstart Taq. The PCR products divided into distinct evolutionary groups comprising were separated on 8% denaturing polyacrylamide gels in two a-crystallins (CRYAA and CRYAB), which belong an Applied Biosystems 377 Sequencer. Genescan (ver- to the small heat shock protein family of molecular sion 3.7) and Genotyper (version 3.7) software packages chaperones and nine b-/c-crystallins (CRYBA1/A3/A4/ (Perkin Elmer Corporation, USA) were used to generate B1/B2/B3 and CRYGC/D/S), which belong to the genotypes. Dinucleotide repeat microsatellite markers family of epidermis-specific differentiation proteins (He were labeled with fluorescent dye. and Li 2000). Connexin genes express intercellular gap junctions that facilitate the cytoplasmic exchange of ions, second messengers, and small metabolites and Linkage analysis and haplotyping preserve lens fiber cell homeostasis (Kumar and Gilula 1996). Major intrinsic protein is the most abundant Genotype data were stored in a family program. A two- junctional membrane protein in the mature lens. It point LOD scores (Z) was calculated using the MLINK minimizes extracellular space in the lens and facilitates subprogram of the LINKAGE package (version 5.1) the formation of specialized membrane junctions with the following assumptions of a gene frequency of between fiber cells (Heymann et al. 1998; Michea et al. 0.0001, a penetrance of 100%, and equal allele fre- 1994). The interaction of the cytoskeletal proteins and quencies. Multipoint analysis was computed using crystallins in the cytoplasm determines the structural FASTMAP. Microsatellite markers, allele frequencies, framework of lens cells, which is important for the and recombination distances between the marker loci maintenance of transparency in the lens (Matsushima were based on the Ge´ne´thon linkage map. Family and et al. 1997). As transcription factors and diffusible haplotype data were processed using Cyrillic (version growth factors, PITX3 and HSF4 play a key role in the 2.1) software. complex development of the lens (Beebe 1994). So far, more and more mutations causing congenital cataract have been discovered. In this study, we mapped the candidate gene to Results chromosome 2p24-pter with a four-generation Chinese family affected by autosomal dominant coralliform Clinical data cataract. The four-generation Chinese family consisted of 27 members, including 11 affected individuals, 7 unaf- fected individuals, and 9 spouses (Fig. 1). The affected Materials and methods members appear in four successive generations, the ratio of affected males to females is 1:1, and male-to- Clinical evaluations male transmission is also involved, which is consistent with autosomal dominant inheritance. The affected Patients in this family who had no cataract extraction individuals in the family had visual handicaps but no were given an examination, which included photogra- family history of any other ocular or systemic phy and slit-lamp microscopy of the lens, to record abnormalities. The age of the affected individuals cataract type. Informed consent was then obtained for varied from 5 to 50 years. In all cases, the cataract 307 Fig. 1 Cataract family and haplotype analysis. Squares and circles symbolize males and females, respectively. Filled symbols denote affected status. The dark bar represents the presumed affected chromosome was congenital, that is, dating from either birth or type of cataract was classified as autosomal dominant infancy. Throughout childhood and early adolescence, coralliform cataract. the affected individuals experienced mild reduction of visual acuity, followed by gradually decreasing visual acuity over time. Thus III:6, III:7, III:11 and III:12 Gene scan and linkage analysis had been obliged to discontinue their studies during elementary school because of slowly deteriorating vi- As a first step, we tested markers on known loci, sion. The proband II:6 underwent cataract extraction which are related to genes involved in lens formation, for both eyes at age 45.
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