PDF(Pubmed)
Abstract：
Diaphanous-related formin 1 (DIAPH1) is a formin homology F-actin elongating protein encoded by DIAPH1. Homozygous recessive variants resulting in the loss of DIAPH1 function cause seizures, cortical blindness, and microcephaly syndrome (SCBMS), but hearing loss has not been reported. In contrast, dominant variants of human DIAPH1 are associated with DFNA1 non-syndromic sensorineural hearing loss. The deafness phenotype is due partly to abnormal F-actin elongation activity caused by disruption of the DIAPH1 autoinhibitory mechanism. We report an elderly female heterozygous for the c.3145C>T: p.R1049X variant who showed late-onset sensorineural hearing loss in her fifth decade. p.R1049X lacks F-actin elongation activity because this variant truncates one-third of the FH2 domain, which is vital for DIAPH1 dimerization and processive F-actin elongation activity. Concordantly, no increase of F-actin or processive F-actin elongation activity was observed after overexpression of p.R1049X DIAPH1 in HeLa cells or by single-molecule microscopy using Xenopus XTC cells. However, overexpression of the p.R1049X variant impairs formation of cell-cell junctions and mitosis. We speculate that late-onset hearing loss is a long-term consequence of heterozygosity for the recessive p.R1049X variant, a phenotype that may have been overlooked among carriers of other recessive alleles of DIAPH1.
摘要：
透明相关形式素1（DIAPH1）是DIAPH1编码的形式素同源性F-肌动蛋白延伸蛋白。导致DIAPH1功能丧失的纯合隐性变异导致癫痫发作，皮质失明,和小头畸形综合征（SCBMS），但听力损失尚未报告。相比之下,人DIAPH1的显性变异与DFNA1非综合征性感觉神经性听力损失相关。耳聋表型部分是由于DIAPH1自动抑制机制的破坏引起的F-肌动蛋白伸长活性异常。我们报告了一名c.3145C>T：p.R1049X变体的老年女性杂合子，她在第五个十年中表现出迟发性感觉神经性听力损失。p.R1049X缺乏F-肌动蛋白延伸活性，因为该变体截短了FH2结构域的三分之一，这对于DIAPH1二聚化和进行性F-肌动蛋白延伸活性至关重要。和谐地，在HeLa细胞中过表达p.R1049XDIAPH1后，或使用非洲爪狼XTC细胞通过单分子显微镜观察，未观察到F-肌动蛋白或进行性F-肌动蛋白延伸活性的增加。然而,p.R1049X变体的过表达损害细胞-细胞连接和有丝分裂的形成。我们推测，迟发性听力损失是隐性p.R1049X变体杂合性的长期结果，在DIAPH1其他隐性等位基因携带者中可能被忽视的表型。
