Damji K F, Sohocki M M, Khan R, Gupta S K, Rahim M, Loyer M, Hussein N, Karim N, Ladak S S, Jamal A, Bulman D, Koenekoop R K
Ottawa Hospital Research Institute, Ont.
Can J Ophthalmol. 2001 Aug;36(5):252-9. doi: 10.1016/s0008-4182(01)80018-1.
Leber's congenital amaurosis (LCA) represents the earliest and severest form of retinal dystrophy leading to congenital blindness. A total of 20% of children attending blind schools have this disease. LCA has a multigenic basis and is proving central to our understanding of the development of the retina. We describe the clinical and molecular genetic features of four inbred pedigrees from neighbouring remote villages in northern Pakistan, in which some of the affected members have concurrent keratoconus.
History-taking and physical and eye examinations were performed in the field. Venipuncture, DNA extraction, studies of linkage to known LCA genes, automated sequencing and polymorphism analyses for haplotype assessments were done.
We examined 12 affected and 15 unaffected family members. By history, there were an additional nine blind people in the four pedigrees. In each pedigree a consanguineous marriage was evident. We found a homozygous nonsense mutation in the AIPL1 gene, which replaces a tryptophan with a stop codon (Trp278X). The phenotype is severe and variable, despite the common molecular genetic etiology in each family. Affected patients had hand motion to no light perception vision and fundus findings ranging from maculopathy to diffuse pigmentary retinopathy. Three affected members had definite keratoconus, and two were suspects based on mild cone formation in the cornea of at least one eye.
We have identified four Pakistani families with a severe form of LCA that is associated with severe keratoconus in some affected members. The molecular etiology in all four families is a homozygous nonsense mutation, Trp278X, in the photoreceptor-pineal gene AIPL1. To our knowledge, this is one of the first phenotype-genotype correlations of AIPL1-associated LCA.
莱伯先天性黑矇（LCA）是视网膜营养不良最早期、最严重的形式，可导致先天性失明。在盲人学校就读的儿童中，共有20%患有此病。LCA具有多基因基础，并且在我们对视网膜发育的理解中起着核心作用。我们描述了来自巴基斯坦北部相邻偏远村庄的四个近亲家系的临床和分子遗传学特征，其中一些受影响成员同时患有圆锥角膜。
在现场进行病史采集、体格检查和眼部检查。进行静脉穿刺、DNA提取、与已知LCA基因的连锁研究、自动测序以及用于单倍型评估的多态性分析。
我们检查了12名受影响和15名未受影响的家庭成员。根据病史，这四个家系中还有另外9名盲人。在每个家系中，近亲结婚都很明显。我们在AIPL1基因中发现了一个纯合无义突变，该突变用一个终止密码子取代了色氨酸（Trp278X）。尽管每个家庭的分子遗传病因相同，但表型严重且多变。受影响的患者视力从手动到无光感，眼底表现从黄斑病变到弥漫性色素性视网膜病变不等。三名受影响成员患有明确的圆锥角膜，两名基于至少一只眼角膜轻度圆锥形成而疑似患病。
我们鉴定出四个患有严重形式LCA的巴基斯坦家庭，其中一些受影响成员患有严重圆锥角膜。所有四个家庭的分子病因都是光感受器 - 松果体基因AIPL1中的纯合无义突变Trp278X。据我们所知，这是AIPL1相关LCA的首批表型 - 基因型相关性研究之一。
