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首页> 外文期刊>BMC Ophthalmology >Mutation spectrum of the FZD-4 , TSPAN12 AND ZNF408 genes in Indian FEVR patients
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Mutation spectrum of the FZD-4 , TSPAN12 AND ZNF408 genes in Indian FEVR patients

机译：印度FEVR患者FZD-4，TSPAN12和ZNF408基因突变谱

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Background Mutations in candidate genes that encode for a ligand ( NDP ) and receptor complex ( FZD4, LRP5 and TSPAN12 ) in the Norrin β-catenin signaling pathway are involved in the pathogenesis of familial exudative vitreoretinopathy (FEVR, MIM # 133780). Recently, a transcription factor ( ZNF408 ) has also been implicated in FEVR. We had earlier characterized the variations in NDP among FEVR patients from India. The present study aimed at understanding the involvement of the remaining genes ( FZD4 , TSPAN12 and ZNF408 ) in the same cohort. Methods The DNA of 110 unrelated FEVR patients and 115 unaffected controls were screened for variations in the entire coding and untranslated regions of these 3 genes by resequencing. Segregation of the disease-associated variants was assessed in the family members of the probands. The effect of the observed missense changes were further analyzed by SIFT and PolyPhen-2 scores. Results The screening of FZD4, TSPAN12 and ZNF408 genes identified 11 different mutations in 15/110 FEVR probands. Of the 11 identified mutations, 6 mutations were novel. The detected missense mutations were mainly located in the domains which are functionally crucial for the formation of ligand-receptor complex and as they replaced evolutionarily highly conserved amino acids with a SIFT score?Conclusions Our genetic screening revealed varying mutation frequencies in the FZD4 (8.0?%) , TSPAN12 (5.4?%) and ZNF408 (2.7?%) genes among the FEVR patients, indicating their potential role in the disease pathogenesis. The observed mutations segregated with the disease phenotype and exhibited variable expressivity. The mutations in FZD4 and TSPAN12 were involved in autosomal dominant and autosomal recessive families and further validates the involvement of these gene in FEVR development.
机译：背景在Norrinβ-catenin信号通路中编码配体（NDP）和受体复合物（FZD4，LRP5和TSPAN12）的候选基因中的突变与家族性渗出性玻璃体视网膜病变（FEVR，MIM＃133780）的发病机理有关。最近，在FEVR中还涉及转录因子（ZNF408）。我们较早地表征了印度FEVR患者中NDP的变化。本研究旨在了解同一队列中其余基因（FZD4，TSPAN12和ZNF408）的参与。方法通过重新测序，筛选110例无关FEVR患者和115例未患病对照的DNA，以检测这3个基因的整个编码区和非翻译区的变异。在先证者的家庭成员中评估与疾病相关的变体的隔离。通过SIFT和PolyPhen-2分数进一步分析了观察到的错义变化的影响。结果对FZD4，TSPAN12和ZNF408基因的筛选确定了15/110 FEVR先证者中的11个不同突变。在确定的11个突变中，有6个是新颖的突变。检测到的错义突变主要位于对配体-受体复合物的形成起关键作用的结构域中，因为它们用SIFT分数代替了进化上高度保守的氨基酸？结论我们的遗传筛选显示FZD4（8.0？ FEVR患者中的TSPAN12（5.4％）和ZNF408（2.7％）基因，表明它们在疾病发病机理中的潜在作用。观察到的突变与疾病表型分离并表现出可变的表达。 FZD4和TSPAN12中的突变与常染色体显性家族和常染色体隐性家族有关，进一步证实了这些基因与FEVR发育有关。

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