ACTG1 – Autosomal Dominant Nonsyndromic Hearing Loss

ACTG1 encodes γ-actin, a major cytoskeletal protein in cochlear hair cells whose normal function is essential for stereocilia integrity and auditory transduction (PMID:29620237). Heterozygous missense mutations in ACTG1 cause DFNA20/26, an autosomal dominant nonsyndromic hearing loss phenotype characterized by progressive sensorineural impairment, with occasional congenital onset.

Genetic Evidence

Seventeen distinct missense variants have been reported in 20 unrelated families with DFNA20/26, all demonstrating autosomal dominant inheritance (PMID:29620237). The novel c.94C>T (p.Pro32Ser) variant was identified in a small pedigree with congenital hearing loss by newborn screening (PMID:29620237). Additional recurrent variants include c.833C>T (p.Thr278Ile) in a multigenerational kindred (PMID:14684684), c.1109T>C (p.Val370Ala) in a Norwegian family with progressive deafness (PMID:16773128), and c.364A>G (p.Ile122Val) in a Chinese pedigree (PMID:18804074).

Segregation

Co-segregation of ACTG1 missense alleles with hearing loss has been demonstrated across multiple multiplex pedigrees, encompassing at least 20 affected relatives (segregation data from PMID:29620237 and PMID:16773128).

Variant Spectrum

All pathogenic variants to date are missense changes clustering within actin’s core domains that alter protein–protein interfaces critical for F-actin stability. No loss-of-function or splice alterations have been reported, consistent with a gain-of-function or dominant-negative mechanism.

Functional Evidence

Yeast and mammalian cell assays of p.Thr278Ile, p.Val370Ala, p.Lys118Met, and p.Pro332Ala demonstrate aberrant F-actin dynamics, including increased cofilin-mediated severing and filament instability (PMID:19419963). In vitro polymerization and cell-based rescue experiments confirm that these mutations compromise γ-actin assembly, supporting a pathogenic mechanism of cytoskeletal destabilization.

Integration and Conclusion

Collectively, robust genetic and functional data over two decades substantiate a definitive gene–disease relationship between ACTG1 and autosomal dominant nonsyndromic hearing loss. The preponderance of missense alleles, consistent segregation in multiple pedigrees, and concordant functional impairment of γ-actin polymerization underpin clinical validity. Genetic testing for ACTG1 variants enables precise diagnosis and informs family counseling.

Key Take-home: ACTG1 missense mutations cause DFNA20/26 via dominant-negative disruption of γ-actin filaments, and should be included in diagnostic panels for sensorineural hearing loss.

References

• Molecular medicine reports • 2018 • A novel missense mutation in the ACTG1 gene in a family with congenital autosomal dominant deafness: A case report. PMID:29620237
• Journal of medical genetics • 2003 • A mutation in the gamma actin 1 (ACTG1) gene causes autosomal dominant hearing loss (DFNA20/26). PMID:14684684
• European journal of human genetics • 2006 • A novel missense mutation in ACTG1 causes dominant deafness in a Norwegian DFNA20/26 family, but ACTG1 mutations are not frequent among families with hereditary hearing impairment. PMID:16773128
• Journal of genetics and genomics • 2008 • Novel ACTG1 mutation causing autosomal dominant non-syndromic hearing impairment in a Chinese family. PMID:18804074
• The Journal of biological chemistry • 2009 • Allele-specific effects of human deafness gamma-actin mutations (DFNA20/26) on the actin/cofilin interaction. PMID:19419963

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