Constitutive activation of DIA 1 ( DIAPH 1) 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 (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.

Remodeling of the Inner Hair Cell Microtubule Meshwork in a Mouse Model of Auditory Neuropathy AUNA1

“…It is therefore tempting to propose a similar scenario in this form of hearing impairment, i.e., an alteration of the apical pole of the hair cells. Consistently, transgenic mouse model of DFNA1 shows sparse and fused stereociliary bundle (Ueyama et al, 2016). …”

Fhod1, an actin‐organizing formin family protein, is dispensable for cardiac development and function in mice

“…Through cooperation of the two domains, formins contribute to various biological functions via regulation of actin dynamics. The physiological significance of formins is exemplified by the fact that mutations in human formins are linked to various human diseases including hearing loss (Lynch et al, 1997;Ueyama et al, 2016), nephrotic syndrome (Brown et al, 2010), cardiomyopathies (Arimura et al, 2013;Wooten et al, 2013), and intellectual disability (Law et al, 2014).…”

Hearing vulnerability after noise exposure in a mouse model of reactive oxygen species overproduction

“…For quantitative assessment of immunoreactive bands, ImageJ software (National Institutes of Health) was used as previously described (Ueyama et al . ). Protein expression levels were normalized to those of tubulinα, actin‐β, or GAPDH.…”

“…Immunoreactivity was detected using the enhanced chemiluminescence (ECL) detection system (Bio-Rad Laboratories, Hercules, CA, USA). For quantitative assessment of immunoreactive bands, ImageJ software (National Institutes of Health) was used as previously described (Ueyama et al 2016). Protein expression levels were normalized to those of tubulina, actin-b, or GAPDH.…”