What it is
In an extended Palestinian kindred, the authors traced autosomal recessive congenital hearing loss to a homozygous FMN1 variant (c.2162-2A>G) that causes aberrant splicing, nonsense-mediated decay, and loss of detectable formin-1 protein, giving the first human phenotype for mutation of this gene. The hearing loss is bilateral, moderate, and stable, accompanied by light hair and no other anomalies. A Fmn1 knockout mouse reproduced the hearing loss and showed disorganized cochlear supporting cells (Deiters' and pillar cells) with loss of tightly bundled microtubule architecture, reduced ABR wave I amplitudes, and fewer auditory nerve fibers, placing FMN1 among the more than 200 genes essential for mammalian hearing.
Why it matters
Formin defects were known to cause neurologic, renal, reproductive, and cardiac disorders, but FMN1, the first-identified formin, had no described human phenotype. This work supplies one, hearing loss, and pairs the human genetics with a mouse model to propose a mechanism in which loss of formin-1 disrupts the microtubule architecture of cochlear supporting cells and compromises the mechanics of the organ of Corti.
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Filed underCellular Mechanics and Interactions, Muscle Physiology and Disorders, Wnt/β-catenin signaling in development and cancer