Biallelic Loss-of-Function Variants in BICD1 Are Associated with Peripheral Neuropathy and Hearing Loss.
Biallelic Loss-of-Function Variants in BICD1 Are Associated with Peripheral Neuropathy and Hearing Loss.
复制标题
BICD1中的双重功能丧失变体与周围神经病和听力损失有关。
DOI：
10.3390/ijms24108897
复制
发表时间：
2023-05-17
影响因子：
5.6
通讯作者：
Booth, Kevin T. A.
中科院分区：
文献类型：
--
作者：
Hirsch, Yoel;Chung, Wendy K. K.;Novoselov, Sergey;Weimer, Louis H.;Rossor, Alexander;LeDuc, Charles A.;McPartland, Amanda J.;Cabrera, Ernesto;Ekstein, Josef;Scher, Sholem;Nelson, Rick F.;Schiavo, Giampietro;Henderson, Lindsay B.;Booth, Kevin T. A.
听力损失和周围神经病是两种临床实体，在遗传和表型上是不同的，有时是共存的。利用外显子组测序和靶向分离分析，我们调查了一个大型德系犹太人家庭周围神经病和听力损失的遗传病因。此外，我们通过免疫印迹法评估了来自患病个体和未患病对照的成纤维细胞裂解产物的候选蛋白的产生。与听力损失和周围神经病变相关的已知疾病基因的致病变异被排除在外。在先证者中发现了BICD1基因的纯合子移码突变c.1683dup(p.(Arg562Thrfs*18))，并分离出该家系中的听力损失和周围神经病。来自患者成纤维细胞的BIDC1RNA分析显示，与对照组相比，基因转录本略有减少。相反，在纯合子c.1683dup个体的成纤维细胞中不能检测到蛋白质，而在未受影响的个体中检测到BICD1。我们的发现表明，BICD1的双等位功能丧失变异与听力损失和周围神经病变有关。BICD1双等位基因功能丧失变异导致周围神经病变和听力损失的确凿证据需要鉴定具有相同表型的类似变异的其他家庭和个人。
Hearing loss and peripheral neuropathy are two clinical entities that are genetically and phenotypically heterogeneous and sometimes co-occurring. Using exome sequencing and targeted segregation analysis, we investigated the genetic etiology of peripheral neuropathy and hearing loss in a large Ashkenazi Jewish family. Moreover, we assessed the production of the candidate protein via western blotting of lysates from fibroblasts from an affected individual and an unaffected control. Pathogenic variants in known disease genes associated with hearing loss and peripheral neuropathy were excluded. A homozygous frameshift variant in the BICD1 gene, c.1683dup (p.(Arg562Thrfs*18)), was identified in the proband and segregated with hearing loss and peripheral neuropathy in the family. The BIDC1 RNA analysis from patient fibroblasts showed a modest reduction in gene transcripts compared to the controls. In contrast, protein could not be detected in fibroblasts from a homozygous c.1683dup individual, whereas BICD1 was detected in an unaffected individual. Our findings indicate that bi-allelic loss-of-function variants in BICD1 are associated with hearing loss and peripheral neuropathy. Definitive evidence that bi-allelic loss-of-function variants in BICD1 cause peripheral neuropathy and hearing loss will require the identification of other families and individuals with similar variants with the same phenotype.
登录
查看更多内容
影响因子：
4.6
作者：
Aguirre-Chen, Cristina;Buelow, Hannes E.;Kaprielian, Zaven
通讯作者：
Kaprielian, Zaven
影响因子：
3.5
作者：
Carrera, Lilian A. Martinez;Gabriel, Elke;Wirth, Brunhilde
通讯作者：
Wirth, Brunhilde
影响因子：
30.8
作者：
Havrilla, James M.;Pedersen, Brent S.;Quinlan, Aaron R.
通讯作者：
Quinlan, Aaron R.
影响因子：
9.8
作者：
Neveling, Kornelia;Martinez-Carrera, Lilian A.;Wirth, Brunhilde
通讯作者：
Wirth, Brunhilde
影响因子：
9.8
作者：
Oates, Emily C.;Rossor, Alexander M.;Reilly, Mary M.
通讯作者：
Reilly, Mary M.