Mutations in the gamma-actin gene (ACTG1) are associated with dominant progressive deafness (DFNA20/26)

Abstract

Age-related hearing loss (presbycusis) is a significant problem in the population. The genetic contribution to age-related hearing loss is estimated to be 40%-50%. Gene mutations that cause nonsyndromic progressive hearing loss with early onset may provide insight into the etiology of presbycusis. We have identified four families segregating an autosomal dominant, progressive, sensorineural hearing loss phenotype that has been linked to chromosome 17q25.3. The critical interval containing the causative gene was narrowed to approximately 2 million bp between markers D17S914 and D17S668. Cochlear-expressed genes were sequenced in affected family members. Sequence analysis of the gamma-actin gene (ACTG1) revealed missense mutations in highly conserved actin domains in all four families. These mutations change amino acids that are conserved in all actins, from protozoa to mammals, and were not found in >100 chromosomes from normal hearing individuals. Much of the specialized ultrastructural organization of the cells in the cochlea is based on the actin cytoskeleton. Many of the mutations known to cause either syndromic or nonsyndromic deafness occur in genes that interact with actin (e.g., the myosins, espin, and harmonin). The mutations we have identified are in various binding domains of actin and are predicted to mildly interfere with bundling, gelation, polymerization, or myosin movement and may cause hearing loss by hindering the repair or stability of cochlear cell structures damaged by noise or aging. This is the first description of a mutation in cytoskeletal, or nonmuscle, actin.

Figure 1

Families with autosomal dominant hearing loss linked to chromosome 17q25. Left, pedigrees of four families segregating highly penetrant autosomal dominant, sensorineural, postlingual hearing loss. Asterisks (*) indicate the persons in each pedigree who received audiological testing. The 21-year-old recombinant in family MSUDF1 who allowed refinement of the critical interval is indicated by an unfilled arrow; probands are indicated by filled arrows. Right, threshold data from the better ears of representative patients. Ages at testing are noted to the right of the audiograms. The individuals used to provide the graphic data are denoted by a star in families 1250 and 1320 and by their ages in family MSUDF1 and kindred 6.

Figure 2

γ-Actin mutation analyses. A, Genomic structure of γ-actin showing the mature mRNA sequence in large blocks. There is a 5′ noncoding exon and a substantial 3′ UTR. The position of the mutations is identified with a down-pointing arrow (↓), and the primers used for sequencing are indicated. B, Sequence results for each of the mutations. Each mutation is heterozygous in affected individuals. C, Structural model of actin (Kabsch et al. 1990) showing the positions of the amino acids that are altered in families with DFNA20/26.

Figure 3

Conservation of actin proteins. MultAlin view of cytoplasmic actin molecules from various species. The top five sequences are γ-actin from human, mouse, bovine, frog, and rabbit, respectively, followed by chicken and goldfish β-actin, shrimp actin, fruitfly actin 5c, silkworm actin A4, and nematode actin. Human β-actin differs from γ-actin in that it carries an E at the N-terminal positions marked with asterisks (*) and a V at the position marked with a number sign (#).