MYO15A – Autosomal Recessive Nonsyndromic Hearing Loss 3

MYO15A encodes the unconventional myosin XVA motor protein essential for stereocilia elongation in cochlear hair cells. Biallelic loss-of-function and hypomorphic variants in MYO15A underlie autosomal recessive nonsyndromic hearing loss type 3 (DFNB3), characterized by congenital severe-to-profound sensorineural hearing impairment with preserved vestibular function. Cochlear implantation often yields favorable outcomes, consistent with residual hair cell activity despite disrupted stereocilia architecture.

Extensive genetic studies have identified pathogenic MYO15A variants in large consanguineous and outbred cohorts. A Tunisian linkage analysis of 77 families revealed homozygous nonsense (c.4998C>A (p.Cys1666Ter)) and canonical splice-site (c.9229+1G>A) variants in two families, and additional non-canonical splice-site changes in a third (PMID:19309289). Follow-up of a previously ascertained pedigree added a third affected sibling compound heterozygous for c.8375C>T (p.Val2792Ala) and a novel splice-site variant c.5531+1G>C (PMID:36401330), confirming segregation across three affected individuals.

Targeted and exome sequencing across diverse populations uncovered 11 variants in 10 unrelated DFNB3 probands, including novel frameshift c.900delT (p.Pro301ArgfsTer143) and nonsense c.4879G>T (p.Glu1627Ter) alleles. Phenotype–genotype correlation showed that N-terminal truncating or second FERM-domain missense variants confer residual low-frequency hearing, enabling feasible acoustic or electroacoustic stimulation (PMID:33784549).

A recent Iranian cohort study of 26 unrelated families identified 27 distinct MYO15A variants—10 novel and 17 previously reported—with an equal distribution of truncating and splice defects, further expanding the allelic spectrum and reinforcing the recessive inheritance model (PMID:40275102).

Functional assays demonstrate that pathogenic MYO15A variants disrupt stereocilia targeting and elongation. In epithelial cell models, mutant myosin XVA fails to accumulate at microvillar tips, mirroring impaired stereocilia architecture (PMID:20505086). A mouse knock-in of the p.Arg828Ter variant recapitulates human hair cell morphology defects and hearing loss, confirming haploinsufficiency as the pathogenic mechanism (PMID:40126902).

Collectively, genetic and experimental data robustly support a definitive association between MYO15A and DFNB3. The identification of recurrent and private variants across populations, concordant segregation, and phenotypic rescue by cochlear implantation emphasize the clinical utility of MYO15A testing for precise molecular diagnosis, genetic counseling, and tailored auditory rehabilitation.

References

• Genetic Testing and Molecular Biomarkers • 2009 • Screening of the DFNB3 locus: identification of three novel mutations of MYO15A associated with hearing loss and further suggestion for two distinctive genes on this locus. PMID:19309289
• BMC Medical Genomics • 2022 • Addition of an affected family member to a previously ascertained autosomal recessive nonsyndromic hearing loss pedigree and systematic phenotype-genotype analysis of splice-site variants in MYO15A. PMID:36401330
• Hearing Research • 2021 • Heterogeneity of MYO15A variants significantly determine the feasibility of acoustic stimulation with hearing aid and cochlear implant. PMID:33784549
• Scientific Reports • 2025 • The clinical and genetic spectrum of twenty-six individuals with hearing loss affected by MYO15A variants. PMID:40275102
• The Journal of Neuroscience • 2010 • Targeting of the hair cell proteins cadherin 23, harmonin, myosin XVa, espin, and prestin in an epithelial cell model. PMID:20505086
• Acta Oto-Laryngologica • 2025 • The 133-kDa N-terminal region of myosin XVa is critical for normal structure and function of auditory and hair cells. PMID:40126902

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