A novel COL4A1 gene mutation results in autosomal dominant non-syndromic congenital cataract in a Chinese family

Xia et al. BMC Medical Genetics 2014, 15:97 http://www.biomedcentral.com/1471-2350/15/97 RESEARCH ARTICLE Open Access A novel COL4A1 gene mutation results in autosomal dominant non-syndromic congenital cataract in a Chinese family Xin-Yi Xia1†, Na Li1†, Xiang Cao1, Qiu-Yue Wu1, Tian-Fu Li2, Cui Zhang1, Wei-Wei Li1, Ying-Xia Cui1, Xiao-Jun Li1* and Chun-Yan Xue3* Abstract Background: Almost one-third of congenital cataracts are primarily autosomal dominant disorders, which are also called autosomal dominant congenital cataract, resulting in blindness and clouding of the lens. The purpose of this study was to identify the disease-causing mutation in a Chinese family affected by bilateral, autosomal dominant congenital cataract. Methods: The detection of candidate gene mutation and the linkage analysis of microsatellite markers were performed for the known candidate genes. Molecular mapping and cloning of candidate genes were used in all affected family members to screen for potential genetic mutations and the mutation was confirmed by single enzyme digestion. Results: The proband was diagnosed with isolated, congenital cataract without the typical clinical manifestations of cataract, which include diabetes, porencephaly, sporadic intracerebral hemorrhage, and glomerulopathy. A novel mutation, c.2345 G > C (Gly782Ala), in exon 31 of the collagen type IV αlpha1 (COL4A1) gene, which encodes the collagen alpha-1(IV) chain, was found to be associated with autosomal dominant congenital cataract in a Chinese family. This mutation was not found in unaffected family members or in 200 unrelated controls. Sequence analysis confirmed that the Gly782 amino acid residue is highly conserved. Conclusions: The novel mutation (c.2345 G > C) of the COL4A1 gene is the first report of a non-syndromic, autosomal dominant congenital cataract, thereby highlighting the important role of type IV collagen in the physiological and optical properties of the lens. Keywords: Type IV collagen, COL4A1, Non-syndromic congenital cataract Background Almost one-third of congenital cataracts, also referred to as autosomal dominant congenital cataract (ADCC), are primarily autosomal dominant disorders that result in blindness and clouding of the lens. Such disorders account for 10% of all childhood blindness worldwide. * Correspondence: ; † Equal contributors 1 Institute of Laboratory Medicine, Jinling Hospital, Nanjing University School of Medicine, 305 East Zhongshan Road, Nanjing 210002, People’s Republic of China 3 Department of Ophthalmology, Jinling Hospital, Nanjing University School of Medicine, 305 East Zhongshan Road, Nanjing 210002, People’s Republic of China Full list of author information is available at the end of the article Additionally, there are a few reports of such disorders being inherited in an autosomal recessive or X-linked manner [1]. ADCC has highly variable morphologies (including total, polar, zonular, and capsular) within families and can include multisystem disorders, such as Wolf-Hirschhorn syndrome, SHORT syndrome, Abruzzo-Erickson syndrome [2], and HANAC syndrome [3]. The clinical manifestation of congenital cataract is multi-organs, including myopathy, cerebral hemorrhages, porencephaly, nephropathy, diabetes, etc. In general, nonsyndromic, congenital cataracts that are not related to other disorders are rare, having an estimated frequency of 1–6 per 10,000 live births in industrialized countries, with onethird of cases having a positive family history [3,4] and © 2014 Xia et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Xia et al. BMC Medical Genetics 2014, 15:97 http://www.biomedcentral.com/1471-2350/15/97 5–15 per 10,000 live births in the poorest areas of the world [3,5]. To date, a series of congenital cataractassociated chromosomal locations have been mapped and over 30 genes have been identified by linkage analysis. Most of these genes include crystalline genes (CRYAA, CRYAB, CRYBB1, CRYBB2, CRYBB3, CYRBA1, CRYBA3, CRYBA4, CRYGA, CRYGB, CRYGC, CRYGD, and CRYGS) [6], membrane transport genes (MIP) [7], and gap junction proteins (GJA3 and GJA8) [8]. The remaining known mutations are found in genes encoding growth and transcription factors, such as HSF4, MAF, PITX3, and PAX6 [9]. However, it was discovered that COL4A1 gene mutations were associated with ADCC in French families [10,11], and there were rare reports that the type IV collagen, αlpha1 (COL4A1) gene was associated with non-syndromic, autosomal dominant congenital cataract. COL4A1 (NM_001845) and COL4A2 (NM_001846) encode type IV collagen, which is present in almost all basement membranes and is highly conserved across species, and comprise 52 and 48 exons, respectively. They are arranged head-to-head on opposite strands of human chromosome 13. They are separated by 127 nucleotides containing a shared, bi-directional promoter that requires additional elements to control the tissue specificity and the level of protein expression [12]. Type IV collagen contains three major domains: an amino-terminal 7S domain, which participates in inter-molecular crosslinking and macromolecular organization, and a highly conserved, central triple-helix forming domain and a carboxyl-terminal, non-collagenous domain, which are globular domains responsible for the initiation of heterotrimer assembly [13]. It is known that humans carrying mutations in the COL4A1 locus often exhibit lens abnormalities and cataracts, along with porencephaly, diabetes, sporadic Page 2 of 6 intracerebral hemorrhage and glomerulopathy [6]. However, a mutation of COL4A1 gene resulting in isolated congenital cataract has never been reported previously. Methods Ethics statement The Ethics Committee of Jinling Hospital approved the protocols used in this study. The research adhered to the tenets of the Declaration of Helsinki. All participants gave written consent to participate in the study, including consent to publish any accompanying images. Parental consent was obtained for children under the age of 16 years old. Participant and clinical data The large pedigree (Figure 1) of a five-generation Han family from a rural area in Jiangsu Province in China includes 15 affected and 64 unaffected individuals with typical features of congenital cataract. The proband (IV7) came to our hospital for genetic counseling regarding cataract. All living members of this family underwent a systematic physical inspection and an examination that included slit-lamp microscopy of the lens and brain magnetic resonance imagin (...truncated)