MYO7A – Usher syndrome type 1B

Autosomal recessive variants in MYO7A, encoding the unconventional myosin VIIA motor protein, underlie Usher syndrome type 1B (USH1B), characterized by congenital profound sensorineural hearing loss, vestibular areflexia, and prepubertal retinitis pigmentosa. MYO7A localizes to inner ear hair cell stereocilia and retinal pigment epithelium, where it mediates cargo transport and mechanosensory adaptation. The AR inheritance pattern is supported by segregation of biallelic pathogenic alleles in consanguineous and outbred families. Population screening has not found these variants in healthy controls, confirming their rarity and high penetrance.

Genetic evidence includes identification of MYO7A mutations in over 20 unrelated USH1B families. A heteroduplex screen of 189 independent Usher I cases revealed 23 MYO7A mutations in 20 pedigrees, including 6 premature stop codons, 6 missense, and one splice defect; recurrent alleles such as c.635G>A (p.Arg212His) accounted for 31% of mutant chromosomes (PMID:8900236). Compound heterozygotes and homozygotes for distinct truncating variants confirm AR inheritance and allelic heterogeneity. No pathogenic alleles were detected in ≥96 controls, underscoring specificity.

Segregation analysis demonstrates co-segregation of biallelic MYO7A variants with USH1B in multiple families (PMID:8900236). Across studies, 20 affected relatives have been documented with confirmed biallelic genotypes. Variant spectrum encompasses missense, nonsense, frameshift, splice-site, and large in-del events distributed throughout motor, IQ, and tail domains, with population-specific haplotypes but no single founder globally.

Functional assays support a loss-of-function mechanism: USH1B-associated missense mutations (e.g., c.1190C>A (p.Ala397Asp), c.1348G>C (p.Glu450Gln), c.73G>C (p.Gly25Arg), c.905G>A (p.Arg302His)) abolished actin-activated ATPase activity of human myosin VIIA in vitro, reducing duty ratio and motor processivity (PMID:18700726). In contrast, a DFNB2-linked allele p.Glu1716del retained stereociliary localization in mouse hair cells, correlating residual function with non-syndromic hearing loss (PMID:18181211).

Although early reports linked MYO7A variants to nonsyndromic DFNB2 and DFNA11 phenotypes, consistent absence of vestibular and retinal findings distinguishes DFNB2 from USH1B, indicating allelic and domain-specific modulation rather than disputed association with USH1B. No studies refute the MYO7A–USH1B link; rather, variable expressivity is seen for hypomorphic alleles.

Integration of genetic and functional data establishes a definitive MYO7A–USH1B association. Comprehensive mutation screening and functional confirmation inform molecular diagnosis, genetic counseling, and future gene therapy designs. Key take-home: MYO7A testing reliably identifies USH1B patients, enabling early audiologic and ophthalmologic interventions.

References

• American journal of human genetics • 1996 • Myosin VIIA mutation screening in 189 Usher syndrome type 1 patients. PMID:8900236
• Biochemistry • 2008 • Impacts of Usher syndrome type IB mutations on human myosin VIIa motor function. PMID:18700726
• Human mutation • 2008 • Mutation spectrum of MYO7A and evaluation of a novel nonsyndromic deafness DFNB2 allele with residual function. PMID:18181211

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