Newly identified genetic mechanism essential for hearing
A new study has identified FMN1 as a gene required for hearing in both humans and mice, revealing a previously unknown 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 through a molecular complex involved in melanosome transport, providing new insight into how disruption of a single gene can lead to both hearing loss, and alterations in hair and skin pigment.
The study was conducted by Lara Kamal, Amal Aburayyan, Roni Hahn, Shahar Taiber, and Suleyman Gulsuner, under the leadership of Moien N. Kanaan of Bethlehem University, Mary-Claire King of the University of Washington and Karen B. Avraham of Tel Aviv University. The findings were published in the Proceedings of the National Academy of Sciences of the United States of America.
The discovery began with an extended Palestinian family in which several children were born with bilateral, moderate hearing loss accompanied by light-colored hair. Genomic analysis revealed that the affected children carried two copies of a rare variant in FMN1 that led to loss of the protein formin-1, encoded by the FMN1 gene. Formins are a family of proteins critical to organizing the cytoskeleton, the internal structural framework that gives cells their shape, mechanical stability, and ability to function. Genetic defects in other formin proteins have been associated with neurological, kidney, reproductive, and cardiac disorders. However, until now, no human disorder had been linked to a genetic defect in FMN1 .
To investigate how loss of formin-1 causes hearing impairment, the team studied a mouse model lacking functional formin-1. These mice were produced in the early 1990s, but their hearing had not ever been examined. The authors found that these mice displayed hearing loss similar to the hearing loss of the human family. The mouse could then be studied to discover the underlying cellular changes within the cochlea, the hearing organ of the inner ear.
Detailed microscopic imaging revealed significant disorganization of two types of supporting cells in the organ of Corti, the sensory structure responsible for hearing. Deiters’ cells and pillar cells normally contain tightly bundled networks of microtubules that provide structural support and contribute to the precise mechanics of sound processing. In mice lacking formin-1, these microtubule bundles were disrupted, and the supporting cells lost their highly organized architecture. The abnormalities emerged early after birth and persisted as the animals aged. The structural disruption was accompanied by reduced activity of the auditory nerve and a lower number of auditory nerve fibers. Together, the findings indicate that loss of formin-1 compromises the mechanical integrity of the organ of Corti and interferes with the transmission of sound information from the cochlea to the brain.
The study also offers a possible explanation for the light hair observed in affected family members. Formin-1 is part of a molecular complex involved in transporting melanosomes, the pigment-containing organelles that contribute to hair and skin color. The researchers suggest that the hearing loss and altered pigmentation may therefore arise through different biological effects of the same genetic defect.
The discovery adds FMN1 to the more than 200 genes known to be essential for normal hearing and expands our understanding of the mechanisms underlying inherited hearing loss. This discovery provides additional evidence for understanding that hearing depends not only on sensory hair cells and auditory neurons, but also on precise organization of supporting cells to maintain the cochlea’s structure and mechanics. As gene therapy for deafness becomes a reality, revealing the underlying genetic causes of hearing loss has become critical to treatment.
Karen Avraham, Dean of the Gray Faculty of Medical and Health Sciences and senior author of the study added: "This work has demonstrated that global partnerships can drive meaningful scientific advances, helping to pave the way for future genetic therapies and interventions.”
The study was supported by the U.S. National Institutes of Health, the Israel Precision Medicine Partnership Program and Breakthrough Research grant, from the Israel Science Foundation, and the Mauerberger Foundation Fund.
Link to the article:
www.pnas.org/doi/10.1073/pnas.2622920123
Proceedings of the National Academy of Sciences