Open AccessConstitutive activation of DIA 1 ( DIAPH 1) via C‐terminal truncation causes human sensorineural hearing loss
Author(s) -
Ueyama Takehiko,
Ninoyu Yuzuru,
Nishio Shinya,
Miyoshi Takushi,
Torii Hiroko,
Nishimura Koji,
Sugahara Kazuma,
Sakata Hideaki,
Thumkeo Dean,
Sakaguchi Hirofumi,
Watanabe Naoki,
Usami Shinichi,
Saito Naoaki,
Kitajiri Shinichiro
Publication year - 2016
Publication title -
embo molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.923
H-Index - 107
eISSN - 1757-4684
pISSN - 1757-4676
DOI - 10.15252/emmm.201606609
Subject(s) - otorhinolaryngology , medicine , otology , head and neck surgery , general surgery , family medicine , library science , surgery , computer science
DIAPH 1 encodes human DIA 1, a formin protein that elongates unbranched actin. The c.3634+1G>T DIAPH 1 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 DIA 1, which interacts with its N‐terminal diaphanous inhibitory domain ( DID ), and may engender constitutive activation of DIA 1. However, the underlying pathogenesis that causes DFNA 1 is unclear. We describe a novel patient‐derived DIAPH 1 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 DIA 1(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 DIA 1(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 DIA 1 autoinhibition; disruption of the DID ‐ DAD interaction and consequent activation of DIA 1(R1204X) causes DFNA 1.