NM_001614.5(ACTG1):c.721G>A (p.Glu241Lys) AND Deafness, autosomal dominant 20

Significance: Likely pathogenic
ClinVar: RCV000019987

Variant: NM_001614.5(ACTG1):c.721G>A (p.Glu241Lys)

Type: Variant
Allele: NM_001614.5(ACTG1):c.721G>A (p.Glu241Lys) 33361
Type: single nucleotide variant
Location: Chr17: 81511269 - assembly GRCh38
Chr17: 79478295 - assembly GRCh37
References: dbSNP: 267606631
OMIM: 102560.0008
UniProtKB/Swiss-Prot: VAR_067826
UniProtKB: P63261#VAR_067826


Disease: Deafness, autosomal dominant 20


    In 4 affected members of a Spanish family with autosomal dominant deafness (604717), Morin et al. (2009) identified heterozygosity for a 721G-A transition in exon 4 of the ACTG1 gene, resulting in a glu241-to-lys (E241K) substitution in subdomain 4. The mutation was not found in 100 normal unrelated Spanish controls. The affected members were referred for hearing loss at school age, with the earliest individual referred at age 6 years. All showed postlingual, bilateral, symmetric, progressive sensorineural hearing loss at mid and high frequencies. In yeast, the E241K mutation resulted in a severe phenotype characterized by a highly compromised ability to grow on glycerol as a carbon source, an aberrant multivacuolar pattern, and deposition of thick F-actin bundles randomly in the cell. The latter feature is consistent with the unusual tendency of the E241K mutant to form bundles in vitro, although this propensity to bundle was neutralized by tropomyosin (TPM1; 191010) and the E241K filament bundles were hypersensitive to severing in the presence of cofilin (CFL1; 601442). In transiently transfected NIH3T3 cells, E241K-mutant actin was normally incorporated into cytoskeleton structures, although cytoplasmic aggregates were also observed indicating an element of abnormality caused by the mutations in vivo. Gene-gun mediated expression of the E241K mutant in mouse cochlear hair cells resulted in no gross alteration in cytoskeletal structures or the morphology of stereocilia. Morin et al. (2009) supported the hypothesis that the postlingual and progressive nature of the DFNA20/26 hearing loss may be the result of a progressive deterioration of the hair cell cytoskeleton over time.