New Gene Discovery Reveals an Essential Role for Formin-1 in Hearing

A new study has identified FMN1 as a gene required for hearing in both humans and mice, revealing for the first time a role for formin-1 in maintaining the microscopic cellular architecture of the inner ear. The findings also point to a connection between FMN1 and pigmentation, providing insight into how disruption of a single gene may lead to both hearing loss and changes in hair and skin pigmentation.

The study was conducted by Lara Kamal, Amal Aburayyan, Roni Hahn, Shahar Taiber, and Suleyman Gulsuner, under the leadership of Prof. Moien N. Kanaan of Bethlehem University, Prof. Mary-Claire King of the University of Washington, and Prof. Karen B. Avraham of Tel Aviv University. The findings were published in Proceedings of the National Academy of Sciences of the United States of America (PNAS).

The discovery began with the study of an extended Palestinian family in which several children were born with bilateral, moderate hearing loss and light-colored hair. Genomic analysis revealed that the affected children carried two copies of a rare FMN1 variant that resulted in the loss of the formin-1 protein encoded by the gene.

Formins are a family of proteins involved in organizing the cytoskeleton, the internal structural framework that helps cells maintain their shape, mechanical stability, and function. Genetic defects in other formin proteins have previously been linked to neurological, renal, reproductive, and cardiac disorders. Until now, however, no human phenotype had been associated with a genetic defect in FMN1.

Changes in the Cellular Architecture of the Inner Ear

To investigate how the loss of formin-1 leads to hearing loss, the researchers examined a mouse model lacking functional formin-1. Although these mice were originally generated in the early 1990s, their hearing had not previously been investigated. The researchers found that the mice exhibited hearing loss similar to that observed in the affected family.

Detailed imaging of the cochlea revealed significant disorganization in two types of supporting cells within the organ of Corti, the sensory structure responsible for hearing. Deiters' cells and pillar cells normally contain tightly organized networks of microtubules that provide structural support and contribute to the precise mechanics required for sound processing. In mice lacking formin-1, these microtubule bundles were disrupted and the supporting cells lost their normal organization.

The abnormalities emerged early after birth and persisted with age. The structural disruption was accompanied by reduced auditory nerve activity and fewer auditory nerve fibers, indicating that loss of formin-1 compromises the mechanical integrity of the organ of Corti and interferes with the transmission of auditory information from the cochlea.

A Possible Link to Pigmentation

The study also offers a possible explanation for the lighter hair and skin pigmentation observed in affected family members. Formin-1 participates in a molecular complex involved in transporting melanosomes, the pigment-containing organelles that contribute to hair and skin color. The researchers suggest that the hearing and pigmentation characteristics may therefore result from different biological effects of the same genetic defect.

The discovery adds FMN1 to more than 200 genes known to be essential for mammalian hearing and expands understanding of the mechanisms underlying inherited hearing loss. It also highlights the importance of the precisely organized supporting cells of the cochlea, alongside sensory hair cells and auditory neurons, in maintaining normal hearing.

Prof. Karen Avraham, Dean of the Gray Faculty of Medical and Health Sciences and senior author of the study, noted that the research demonstrates how international scientific partnerships can advance understanding of hearing loss and help lay the groundwork for future genetic interventions.

The study was supported by the U.S. National Institutes of Health and the Israel Science Foundation.

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