Gu Feng, Zhai Hong, Li Dan, Zhao Luxin, Li Chao, Huang Shangzhi, Ma Xu
Department of Genetics, National Research Institute for Family Planning and Peking Union Medical College, Beijing, China.
Mol Vis. 2007 Sep 11;13:1651-6.
To identify the causitive mutation in a five-generation family with autosomal dominant congenital total cataract.
Clinical and ophthalmological examinations were performed on the affected and unaffected family members. All the members were genotyped with microsatellite markers at loci that were considered to be associated with cataracts. Linkage analysis was performed after genotyping. A mutation was detected by direct sequencing using gene specific primers.
Affected individuals in this family showed total cataract. The disease gene was mapping between to a 15.5 Mb interval bounded by D12S368 and D12S1676. A positive two-point LOD score (3.21 at recombination fraction 0) was obtained for the marker D12S90, flanked by D12S368 and D12S1052, on chromosome 12q13.1-21.1. This chromosome encompasses the Major Intrinsic Protein (MIP, MIP26) of the lens, also called aquaporin 0 (AQP0). Sequencing the coding regions of MIP revealed a C>T transition at nucleotide 97 in exon 1 that caused a substitution of arginine (R) to cysteine (C) at codon 33 (p.R33C). This mutation cosegregated with all affected individuals and was not observed in unaffected or in 100 normal unrelated individuals.
This study has identified the first dominant cataract mutation in MIP that is located outside the phylogenetically conserved transmembrane domain.
在一个患常染色体显性遗传性先天性全白内障的五代家族中鉴定致病突变。
对患病和未患病的家族成员进行临床和眼科检查。使用被认为与白内障相关位点的微卫星标记对所有成员进行基因分型。基因分型后进行连锁分析。使用基因特异性引物通过直接测序检测突变。
该家族中的患病个体表现为全白内障。疾病基因定位于由D12S368和D12S1676界定的15.5 Mb区间内。在12号染色体q13.1 - 21.1上，位于D12S368和D12S1052侧翼的标记D12S90获得了正的两点LOD值（重组率为0时为3.21）。该染色体包含晶状体的主要内在蛋白（MIP，MIP26），也称为水通道蛋白0（AQP0）。对MIP编码区进行测序发现外显子1中第97位核苷酸发生C>T转换，导致密码子33处精氨酸（R）被半胱氨酸（C）取代（p.R33C）。此突变与所有患病个体共分离，在未患病个体或100名正常无关个体中未观察到。
本研究鉴定出MIP中第一个位于系统发育保守跨膜结构域外的显性白内障突变。
