Large-scale study identifies the causative gene for sensorineural hearing.


One infant in every 1000 is diagnosed with sensorineural hearing loss, making it an extremely common hereditary disease. It is also estimated that 25-40% of over-65s suffer from acquired sensorineural hearing loss, or age-related hearing loss, amounting to as many as 10-15 million Japanese people.  Despite this, treatment development for sensorineural hearing loss is not making progress. This is because the inner ear is a delicate and complex sensory organ that is difficult to research in vitro. Currently there is no cure, and using a hearing aid is still the most effective treatment.  Now, a study from researchers at Kyoto University and Kobe University identifies the causative gene for sensorineural hearing loss.  The team state that their study, which successfully replicated the condition using transgenic mice, could potentially be used to develop new treatments for hearing loss. The opensource study is published in the journal EMBO Molecular Medicine.

Previous studies have identified approximately 100 causative genes for sensorineural hearing loss. However, there are many unexplained aspects to the process, such as the type of mutation occurring in these genes, and how this causes hearing impairment. This current study identifies the causative gene for autosomal dominant nonsyndromic sensorineural deafness, DFNA1.

The current study carried out exon analysis on 1120 Japanese patients suffering from hearing impairments of unknown causes. Results show a novel mutation in the genetic make-up of the DIA1 molecule in two families, which is involved in the lengthening of linear actin filaments.  The lab explain that these filaments play an important function in the formation and maintenance of auditory hair and inner ear hair cells. Data findings show that the DIA1 mutant protein created by the mutation is an active form variant that lengthens actin filaments even without external stimulation.

The group also engineered a transgenic mouse that manifests this DIA1 mutant protein.  Results show that the mouse exhibits traits of sensorineural hearing loss, demonstrating progressive deafness, starting in the upper registers when young, and advancing with age until it covered all registers.  The researchers state that roughly one-third of the causative genes for sensorineural hearing loss discovered so far are genes that encode proteins with functions related to actin, just like the gene they have identified. They conclude this means as many as one-third of all sensorineural hearing loss cases are related to actin.

The team surmise that they identify a novel DIAPH1 mutation that generates a mildly active DIA1 mutant due to the disrupted interaction of DIA1; they also show that expression of this mutation in vivo is responsible for progressive deafness.  For the future, the researchers state by using the model transgenic mouse to find the compounds that transform actin functions within the inner ear hair cells, the global medical community could potentially develop new treatment for other strains of hereditary sensorineural hearing loss in addition to DFNA1.

Source: Kobe University Biosignal Research Center

A novel clinical DIAPH1 mutation (c.3610C>T) is found in two unrelated families, resulting in a constitutively active DIA1. Patients and mice expressing the DIA1(R1204X) protein show progressive hearing loss beginning in the high‐frequency range and mimicking a novel DFNA1 subtype.  Constitutive activation of DIA1 (DIAPH1) via C‐terminal truncation causes human sensorineural hearing loss.  KITAJIRI et al 2016.

A novel clinical DIAPH1 mutation (c.3610C>T) is found in two unrelated families, resulting in a constitutively active DIA1. Patients and mice expressing the DIA1(R1204X) protein show progressive hearing loss beginning in the high‐frequency range and mimicking a novel DFNA1 subtype. Constitutive activation of DIA1 (DIAPH1) via C‐terminal truncation causes human sensorineural hearing loss. KITAJIRI et al 2016.

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