2024-03-28T14:13:23Z
https://soar-ir.repo.nii.ac.jp/oai
oai:soar-ir.repo.nii.ac.jp:00020837
2022-12-14T04:18:06Z
461:462
Constitutive activation of DIA1 (DIAPH1) via C-terminal truncation causes human sensorineural hearing loss
Ueyama, Takehiko
Ninoyu, Yuzuru
Nishio, Shin-ya
Miyoshi, Takushi
Torii, Hiroko
Nishimura, Koji
Sugahara, Kazuma
Sakata, Hideaki
Thumkeo, Dean
Sakaguchi, Hirofumi
Watanabe, Naoki
Usami, Shin-ichi
Saito, Naoaki
Kitajiri, Shin-ichiro
© 2016 The Authors. This is an open access article under the terms of the Creative Commons Attribution 4.0 License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
actin
deafness
DIAPH1
DFNA1
stereocilia
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 (RRKR1204-1207) 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.
Article
EMBO MOLECULAR MEDICINE.8(11):1310-1324(2016)
WILEY
2016-10-05
eng
journal article
VoR
http://hdl.handle.net/10091/00021594
https://soar-ir.repo.nii.ac.jp/records/20837
https://www.ncbi.nlm.nih.gov/pubmed/27707755
27707755
https://doi.org/10.15252/emmm.201606609
10.15252/emmm.201606609
1757-4676
AA12488115
EMBO MOLECULAR MEDICINE
8
11
1310
1324
https://soar-ir.repo.nii.ac.jp/record/20837/files/26293369_02.pdf
application/pdf
3.9 MB
2019-09-09