Mutations in TBC1D24, a Gene Associated With Epilepsy, Also Cause Nonsyndromic Deafness DFNB86
Mutations in TBC1D24, a Gene Associated With Epilepsy, Also Cause Nonsyndromic Deafness DFNB86
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DOI：
10.1016/j.ajhg.2013.12.004
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发表时间：
2014-01-02
影响因子：
9.8
通讯作者：
Friedman, Thomas B.
中科院分区：
文献类型：
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作者：
Rehman, Atteeq U.;Santos-Cortez, Regie Lyn P.;Friedman, Thomas B.
遗传性耳聋在临床和遗传上是异质性的。我们最近将与非综合征性耳聋相关的基因座DFNB 86定位到染色体16 p上。在这项研究中，全外显子组测序进行了基因组DNA从受影响的个人从三个大的血缘关系的家庭，其中标记与DFNB 86分离与深度耳聋。这些数据的分析显示，纯合突变的TBC1D24中的c.208G>T（p.Asp70Tyr）或c.878G>C（p.Arg293Pro）是三个家庭中耳聋的潜在原因。在另一个耳聋与DFNB 86分离的大家族中，TBC 1 D24的桑格序列分析发现了c.208 G>T（p.Asp70 Tyr）取代。这些突变影响TBC1D24氨基酸残基，这些氨基酸残基在从果蝇到人类的直系同源物中是保守的。在单核苷酸变异数据库或来自种族匹配对照受试者的634条染色体中均未观察到这两种变异。TBC1D24在小鼠内耳中主要定位于螺旋神经节神经元，表明DFNB 86耳聋可能是一种听神经病谱系障碍。此前，据报道，TBC1D24中的6个隐性突变可导致癫痫发作（未报告听力损失），严重程度从正常发育的癫痫到导致儿童死亡的癫痫性脑病不等。我们的四个家庭，其中耳聋分离与突变等位基因的TBC1D24可用于神经系统检查。癫痫和耳聋的共分离在这两个家庭中没有观察到。虽然基因型和表型之间的因果关系目前还不清楚，我们的研究结果，结合已发表的数据，表明TBC1D24的隐性等位基因可以导致癫痫或非综合征性耳聋。
Inherited deafness is clinically and genetically heterogeneous. We recently mapped DFNB86, a locus associated with nonsyndromic deafness, to chromosome 16p. In this study, whole-exome sequencing was performed with genomic DNA from affected individuals from three large consanguineous families in which markers linked to DFNB86 segregate with profound deafness. Analyses of these data revealed homozygous mutation c.208G>T (p.Asp70Tyr) or c.878G>C (p.Arg293Pro) in TBC1D24 as the underlying cause of deafness in the three families. Sanger sequence analysis of TBC1D24 in an additional large family in which deafness segregates with DFNB86 identified the c.208G>T (p.Asp70Tyr) substitution. These mutations affect TBC1D24 amino acid residues that are conserved in orthologs ranging from fruit fly to human. Neither variant was observed in databases of single-nucleotide variants or in 634 chromosomes from ethnically matched control subjects. TBC1D24 in the mouse inner ear was immunolocalized predominantly to spiral ganglion neurons, indicating that DFNB86 deafness might be an auditory neuropathy spectrum disorder. Previously, six recessive mutations in TBC1D24 were reported to cause seizures (hearing loss was not reported) ranging in severity from epilepsy with otherwise normal development to epileptic encephalopathy resulting in childhood death. Two of our four families in which deafness segregates with mutant alleles of TBC1D24 were available for neurological examination. Cosegregation of epilepsy and deafness was not observed in these two families. Although the causal relationship between genotype and phenotype is not presently understood, our findings, combined with published data, indicate that recessive alleles of TBC1D24 can cause either epilepsy or nonsyndromic deafness.