title: Constitutive activation of DIA1 (DIAPH1) via C-terminal truncation causes human sensorineural hearing loss.
abstract: 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.
authors.affiliation: Laboratory of Molecular Pharmacology, Biosignal Research Center, Kobe University, Kobe, Japan tueyama@kobe-u.ac.jp kitajiri@ent.kuhp.kyoto-u.ac.jp.
authors.forename: Takehiko
authors.identifier: 0000-0002-5647-3937
authors.initials: T
authors.lastname: Ueyama
authors.affiliation: Laboratory of Molecular Pharmacology, Biosignal Research Center, Kobe University, Kobe, Japan.
authors.forename: Yuzuru
authors.identifier: 0000-0002-9407-4697
authors.initials: Y
authors.lastname: Ninoyu
authors.affiliation: Department of Otorhinolaryngology, Shinshu University School of Medicine, Matsumoto, Japan.
authors.forename: Shin-Ya
authors.initials: SY
authors.lastname: Nishio
authors.affiliation: Department of Otolaryngology, Head and Neck Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
authors.forename: Takushi
authors.initials: T
authors.lastname: Miyoshi
authors.affiliation: Department of Otolaryngology, Head and Neck Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
authors.forename: Hiroko
authors.initials: H
authors.lastname: Torii
authors.affiliation: Department of Otolaryngology, Head and Neck Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
authors.forename: Koji
authors.initials: K
authors.lastname: Nishimura
authors.affiliation: Department of Otolaryngology, Yamaguchi University Graduate School of Medicine, Ube, Japan.
authors.forename: Kazuma
authors.initials: K
authors.lastname: Sugahara
authors.affiliation: Kawagoe Otology Institute, Kawagoe, Japan.
authors.forename: Hideaki
authors.initials: H
authors.lastname: Sakata
authors.affiliation: Medical Innovation Center, Kyoto University Graduate School of Medicine, Kyoto, Japan.
authors.forename: Dean
authors.initials: D
authors.lastname: Thumkeo
authors.affiliation: Department of Otolaryngology-Head and Neck Surgery, Kyoto Prefectural University of Medicine, Kyoto, Japan.
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Sakaguchi
authors.affiliation: Department of Pharmacology, Kyoto University Graduate School of Medicine, Kyoto, Japan.|Laboratory of Single-Molecule Cell Biology, Kyoto University Graduate School of Biostudies, Kyoto, Japan.
authors.forename: Naoki
authors.initials: N
authors.lastname: Watanabe
authors.affiliation: Department of Otorhinolaryngology, Shinshu University School of Medicine, Matsumoto, Japan.
authors.forename: Shin-Ichi
authors.initials: SI
authors.lastname: Usami
authors.affiliation: Laboratory of Molecular Pharmacology, Biosignal Research Center, Kobe University, Kobe, Japan.
authors.forename: Naoaki
authors.initials: N
authors.lastname: Saito
authors.affiliation: Department of Otolaryngology, Head and Neck Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan tueyama@kobe-u.ac.jp kitajiri@ent.kuhp.kyoto-u.ac.jp.
authors.forename: Shin-Ichiro
authors.initials: SI
authors.lastname: Kitajiri
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D000818:Animals; D002648:Child; D004195:Disease Models, Animal; D005260:Female; D000080865:Formins; D005786:Gene Expression Regulation; D006319:Hearing Loss, Sensorineural / Q000235:genetics* / Q000473:pathology; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D008875:Middle Aged; D017422:Sequence Analysis, DNA
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C108962:DIAPH1 protein, human; D000080865:Formins
keywords: DFNA1; DIAPH1; actin; deafness; stereocilia