Ma Xu, Li Fei-Feng, Wang Shu-Zhen, Gao Chang, Zhang Meng, Zhu Si-Quan
Graduate School, Peking Union Medical College, Beijing, China.
Mol Vis. 2008;14:1906-11. Epub 2008 Oct 24.
We sought to identify the genetic defect in a four-generation Chinese family with autosomal dominant congenital lamellar cataracts and demonstrate the functional analysis with biosoftware of a candidate gene in the family.
Family history data were recorded. Clinical and ophthalmologic examinations were performed on family members. All the members were genotyped with microsatellite markers at loci considered to be associated with cataracts. Two-point LOD scores were calculated by using the Linkage Software after genotyping. A mutation was detected by using gene-specific primers in direct sequencing. Wild type and mutant proteins were analyzed with Online Bio-Software.
Affected members of this family had lamellar cataracts. Linkage analysis was obtained at markers D3S2322 (LOD score [Z]=7.22, recombination fraction [theta]=0.0) and D3S1541 (Z=5.42, theta=0.0). Haplotype analysis indicated that the cataract gene was closely linked to these two markers. Sequencing the beaded filament structural protein 2 (BFSP2) gene revealed a G>A transversion in exon 5, which caused a conservative substitution of Arg to His at codon 339 (P.R339H). This mutation cosegregated with the disease phenotype in all affected individuals and was not observed in the unaffected family members or in 100 normal, unrelated individuals. Bioinformatic analyses showed that a highly conserved region was located around Arg339. Data generated with Online Bio-Software revealed that the mutation altered the protein's hydrophobicity, hydrophobic moment, and chaperone and regulation activities.
This is the first reported case of a congenital lamellar cataract phenotype associated with the mutation of Arg339His (P.R339H) in BFSP2. It highlights the physiologic importance of the beaded filament protein and demonstrates a possible mechanism of action for the mutant gene.
我们试图确定一个四代中国人家族中常染色体显性遗传性先天性板层白内障的基因缺陷，并运用生物软件对该家族中的一个候选基因进行功能分析。
记录家族病史数据。对家族成员进行临床和眼科检查。使用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，使用连锁软件计算两点连锁分析lod值。通过直接测序，使用基因特异性引物检测突变。利用在线生物软件分析野生型和突变型蛋白。
该家族的患病成员患有板层白内障。在标记D3S2322（lod值[Z]=7.22，重组率[θ]=0.0）和D3S1541（Z=5.42，θ=0.0）处获得连锁分析结果。单倍型分析表明，白内障基因与这两个标记紧密连锁。对串珠丝状结构蛋白2（BFSP2）基因进行测序，发现外显子5发生了G>A颠换，导致密码子339处的精氨酸保守替换为组氨酸（P.R339H）。该突变在所有患病个体中与疾病表型共分离，在未患病的家族成员或100名正常无关个体中未观察到。生物信息学分析表明，精氨酸339周围存在一个高度保守区域。在线生物软件生成的数据显示，该突变改变了蛋白质的疏水性、疏水矩以及伴侣和调节活性。
这是首次报道与BFSP2基因中Arg339His（P.R339H）突变相关的先天性板层白内障表型病例。它突出了串珠丝状蛋白的生理重要性，并展示了突变基因可能的作用机制。
