Constitutive activation of DIA1 (DIAPH1) via C-terminal truncation causes human sensorineural hearing loss.
Constitutive activation of DIA1 (DIAPH1) via C-terminal truncation causes human sensorineural hearing loss.
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DOI：
10.15252/emmm.201606609
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发表时间：
2016-11
影响因子：
11.1
通讯作者：
Kitajiri SI
中科院分区：
文献类型：
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作者：
Ueyama T;Ninoyu Y;Nishio SY;Miyoshi T;Torii H;Nishimura K;Sugahara K;Sakata H;Thumkeo D;Sakaguchi H;Watanabe N;Usami SI;Saito N;Kitajiri SI
DIAPH1编码人类DIA1，一种延长未分支肌动蛋白的福尔曼蛋白。C.3634+1G；T DIAPH1突变导致常染色体显性遗传性非综合征性感音神经性耳聋，DFNA1，其特征是从童年开始进行性耳聋。该突变发生在DIA1透明自身调节域(DAD)的C末端附近，与其N端透明抑制域(DID)相互作用，可能导致DIA1的结构性激活。然而，导致DFNA1的潜在发病机制尚不清楚。我们在两个不相关的家系中描述了一种新的患者来源的DIAPH1突变(c.3610C>；T)，该突变导致在DAD C末端的一个碱性氨基酸基序(RRKR 1204-1207)之前提前终止。突变体DIA1(R1204X)破坏了自身抑制的DID-DAD相互作用，并具有结构性活性。这种非计划的活动导致了肌动蛋白聚合的速度增加，并诱导了细长微绒毛的形成。表达标志标记DIA1(R1204X)的小鼠出现进行性耳聋和底部转角毛细胞丢失，并有各种立体纤毛形态异常(短、融合、延长、稀疏)。因此，DAD的碱性区域介导DIA1的自身抑制；DID-DAD相互作用的中断和DIA1(R1204X)的激活导致DFNA1。
DIAPH1 encodes human DIA1, a formin protein that elongates unbranched actin. The c.3634+1G>T DIAPH1 mutation causes autosomal dominant nonsyndromic sensorineural hearing loss, DFNA1, characterized by progressive deafness starting in childhood. The mutation occurs near the C‐terminus of the diaphanous autoregulatory domain (DAD) of DIA1, which interacts with its N‐terminal diaphanous inhibitory domain (DID), and may engender constitutive activation of DIA1. However, the underlying pathogenesis that causes DFNA1 is unclear. We describe a novel patient‐derived DIAPH1 mutation (c.3610C>T) in two unrelated families, which results in early termination prior to a basic amino acid motif (RRKR 1204–1207) at the DAD C‐terminus. The mutant DIA1(R1204X) disrupted the autoinhibitory DID‐DAD interaction and was constitutively active. This unscheduled activity caused increased rates of directional actin polymerization movement and induced formation of elongated microvilli. Mice expressing FLAG‐tagged DIA1(R1204X) experienced progressive deafness and hair cell loss at the basal turn and had various morphological abnormalities in stereocilia (short, fused, elongated, sparse). Thus, the basic region of the DAD mediates DIA1 autoinhibition; disruption of the DID‐DAD interaction and consequent activation of DIA1(R1204X) causes DFNA1.