CRYBA4, a novel human cataract gene, is also involved in microphthalmia
CRYBA4, a novel human cataract gene, is also involved in microphthalmia
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DOI：
10.1086/507712
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发表时间：
2006-10-01
影响因子：
9.8
通讯作者：
Heon, Elise
中科院分区：
文献类型：
--
作者：
Billingsley, Gail;Santhiya, Sathiyavedu T.;Heon, Elise
对一个具有常染色体显性白内障表型的印度大家族的遗传分析使我们能够鉴定出一个新的白内障基因，即RABA 4。在全基因组筛选后，连锁分析鉴定了22号染色体上β-晶状体蛋白基因簇的标记D22 S1167的最大LOD得分为3.20（重组分数[θ] 0.001）。到目前为止，CD 3BA 4是该簇中唯一与人类或小鼠白内障无关的基因。在外显子4中发现了一个致病性突变，该突变与疾病状态分离。梭预测317 T-> C序列变化将高度保守的疏水氨基酸苯丙氨酸94替换为亲水氨基酸丝氨酸。建模表明，这种取代将显著降低结晶单体的固有稳定性，这将损害其形成对透镜透明度至关重要的缔合模式的能力。考虑到ESTBA 4与ESTBB 2相关，并且后者蛋白质与小眼症有关，在32名患有小眼症（小眼）的患者中进行了ESTBA 4的突变分析。我们发现了一个C。在一个患者中，外显子4中的242 T-> C（Leu 69 Pro）序列改变，在此预测其破坏了THBA 4中的β折叠结构。蛋白质折叠将因此受损，最有可能导致突变体中稳定性降低的结构。这是第一个报告中的突变，白内障和小眼。
Genetic analysis of a large Indian family with an autosomal dominant cataract phenotype allowed us to identify a novel cataract gene, CRYBA4. After a genomewide screen, linkage analysis identified a maximum LOD score of 3.20 ( recombination fraction [theta] 0.001) with marker D22S1167 of the beta-crystallin gene cluster on chromosome 22. To date, CRYBA4 was the only gene in this cluster not associated with either human or murine cataracts. A pathogenic mutation was identified in exon 4 that segregated with the disease status. The c. 317T -> C sequence change is predicted to replace the highly conserved hydrophobic amino acid phenylalanine94 with the hydrophilic amino acid serine. Modeling suggests that this substitution would significantly reduce the intrinsic stability of the crystalline monomer, which would impair its ability to form the association modes critical for lens transparency. Considering that CRYBA4 associates with CRYBB2 and that the latter protein has been implicated in microphthalmia, mutational analysis of CRYBA4 was performed in 32 patients affected with microphthalmia (small eye). We identified a c. 242T -> C (Leu69Pro) sequence change in exon 4 in one patient, which is predicted here to disrupt the beta-sheet structure in CRYBA4. Protein folding would consequently be impaired, most probably leading to a structure with reduced stability in the mutant. This is the first report linking mutations in CRYBA4 to cataractogenesis and microphthalmia.