群体凝血因子C同源物基因(Coagulation factor C homology,COCH)是人类发现的第一个伴前庭功能障碍的耳聋基因,位于人类染色体14q12-q13上。迄今,在COCH基因上发现16个位点突变导致常染色体显性遗传非综合征型耳聋DFNA9的发生,其中包括13个非同义单核苷酸多态性(Non-synonymous single nucleotide polymorphisms,nsSNPs)位点。由于该基因其他nsSNPs的基因型与表型关系尚不清楚,因此文章采用生物信息学方法,从COCH基因全部的SNPs中分级筛选,结合已知的致病nsSNPs信息及蛋白三维结构验证,首次预测出由COCH基因编码的cochlin蛋白的vWFA (Von Willebrand factor type A domain)区的8个高风险致病性nsSNPs(I176T、R180Q、G265E、V269L、I368N、I372T、R416C和Y424D)。同时,对位于LCCL (Limulus factor C, cochlin, and late gestation lung protein Lgl1)区域的6个已知致病突变的nsSNPs ( P51S、G87W、I109N、I109T、W117R和F121S)进行了三维结构模拟,发现突变体均发生了环状结构或链状结构的改变。本研究对COCH基因的基因型与表型的相关性研究为遗传性耳聋筛查提供了相应的理论依据,也对该基因所编码的cochlin蛋白的功能研究具有一定的指导意义。
The COCH (Coagulation factor C homology) gene, located in human chromosome 14q12-q13, is the first gene identified to cause vestibular dysfunction. COCH encodes cochlin, which contains an N-terminal LCCL (Limulus factor C, cochlin, and late gestation lung protein Lgl1) domain and a C-temimal vWFA (Von Willebrand factor type A) domain. Recently, functional research of COCH mutations and cochlin have come under the spotlight in the field of hereditary deafness. Approximately 16 mutations in COCH have been confirmed to date, among which 13 non-synonymous single nucleotide polymorphisms (nsSNPs) are the most common form of genetic variations. Nonetheless, there is poor knowledge on the relationship between the genotype and the phenotype of the other nsSNPs in COCH. Here we analyzed deleterious nsSNPs from all SNPs in the COCH gene in the vWFA domain based on different computational methods and identified eight potential pathogenic nsSNPs (I176T, R180Q, G265E, V269L, I368N, I372T, R416C and Y424D) after combining literatures with 3D structures. Meanwhile, the protein structures of six reported pathogenic nsSNPs (P51S, G87W, I109N, I109T, W117R and F121S) in the LCCL domain have been constructed, and we identified aberrant structural changes in loops and chains. The prediction of pathogenic mutations for COCH nsSNPs will provide a blueprint for screening pathogenic mutations, and it will be beneficial to the functional research of COCH and cochlin in this field.
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