Cohen David, Bar-Yosef Udy, Levy Jaime, Gradstein Libe, Belfair Nadav, Ofir Rivka, Joshua Sarah, Lifshitz Tova, Carmi Rivka, Birk Ohad S
The Morris Kahn Laboratory of Human Genetics, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel.
Invest Ophthalmol Vis Sci. 2007 May;48(5):2208-13. doi: 10.1167/iovs.06-1019.
Some 30% of cases of congenital cataract are genetic in origin, usually transmitted as an autosomal dominant trait. The molecular defects underlying some of these autosomal dominant cases have been identified and were demonstrated to be mostly mutations in crystallin genes. The autosomal recessive form of the disease is less frequent. To date, only four genes and three loci have been associated with autosomal recessive congenital cataract. Two extended unrelated consanguineous inbred Bedouin families from southern Israel presenting with autosomal recessive congenital nuclear cataract were studied.
Assuming a founder effect, homozygosity testing was performed using polymorphic microsatellite markers adjacent to each of 32 candidate genes.
A locus on chromosome 22 surrounding marker D22S1167 demonstrated homozygosity only in affected individuals (lod score > 6.57 at theta = 0 for D22S1167). Two crystallin genes (CRYBB1 and CRYBA4) located within 0.1 cM on each side of this marker were sequenced. No mutations were found in CRYBA4. However, an identical homozygous delG168 mutation in exon 2 of CRYBB1 was discovered in affected individuals of both families, generating a frameshift leading to a missense protein sequence at amino acid 57 and truncation at amino acid 107 of the 252-amino-acid CRYBB1 protein. Denaturing [d]HPLC analysis of 100 Bedouin individuals unrelated to the affected families demonstrated no CRYBB1 mutations.
CRYBB1 mutations have been shown to underlie autosomal dominant congenital cataract. The current study showed that a different mutation in the same gene causes an autosomal recessive form of the disease.
约30%的先天性白内障病例起源于遗传,通常以常染色体显性性状遗传。已确定其中一些常染色体显性病例的分子缺陷,并且证明主要是晶状体蛋白基因中的突变。该疾病的常染色体隐性形式较为少见。迄今为止,仅有四个基因和三个基因座与常染色体隐性先天性白内障相关。对来自以色列南部的两个无亲缘关系的近亲结婚的贝都因大家族进行了研究,这两个家族均表现为常染色体隐性先天性核性白内障。
假设存在奠基者效应,使用与32个候选基因相邻的多态性微卫星标记进行纯合性检测。
位于22号染色体上围绕标记D22S1167的一个基因座仅在患病个体中显示纯合性(对于D22S1167,在θ = 0时,连锁对数得分> 6.57)。对位于该标记两侧0.1 cM范围内的两个晶状体蛋白基因(CRYBB1和CRYBA4)进行测序。在CRYBA4中未发现突变。然而,在两个家族的患病个体中均发现CRYBB1外显子2中存在相同的纯合缺失G168突变,导致移码,从而在252个氨基酸的CRYBB1蛋白的第57位氨基酸处产生错义蛋白序列,并在第107位氨基酸处截断。对100名与患病家族无亲缘关系的贝都因个体进行变性高效液相色谱分析,未发现CRYBB1突变。
CRYBB1突变已被证明是常染色体显性先天性白内障的病因。当前研究表明,同一基因中的不同突变会导致该疾病的常染色体隐性形式。