A New Locus for Late-Onset, Progressive, Hereditary Hearing Loss DFNA20 Maps to 17q25

Morell, Robert J.; Friderici, Karen H.; Wei, Sainan; Elfenbein, Jill L.; Friedman, Thomas B.; Fisher, Rachel

doi:10.1006/geno.1999.6058

Cited by 50 publications

(47 citation statements)

References 16 publications

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“…Linkage to this chromosomal region has previously been reported for autosomal-dominant HL and two overlapping hearing impairment locus numbers, DFNA20 and DFNA26, have been assigned to the region. 16,17 Recently, ACTG1 was found to be the causative gene for hearing impairment in this region in five American and Dutch families ( Table 2, online Supplementary material).…”

Section: Resultsmentioning

confidence: 99%

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

et al. 2006

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The c-actin gene (ACTG1) encodes a major cytoskeletal protein of the sensory hair cells of the cochlea. Recently, mutations in ACTG1 were found to cause autosomal dominant, progressive, sensorineural hearing impairment linked to the DFNA20/26 locus on chromosome 17q25.3 in four American families and in one Dutch family. We report here the linkage of autosomal dominant, progressive, sensorineural hearing impairment in a large Norwegian family to the DFNA20/26 locus. Sequencing of ACTG1 identified a novel missense mutation (c.1109T4C; p.V370A) segregating with the hearing loss. Functional analysis in yeast showed that the p.V370A mutation restricts cell growth at elevated temperature or under hyperosmolar stress. Molecular modelling suggested that the p.V370A mutation modestly alters a site for protein -protein interaction in c-actin and thereby modestly alters c-actin-based cytoskeletal structures. Nineteen Norwegian and Danish families with autosomal, dominant hearing impairment were analyzed for mutations in ACTG1 by sequencing, but no disease-associated mutations were identified. Finally, a longterm follow-up of the hearing loss progression associated with the p.V370A mutation in ACTG1 is provided. The present study expands our understanding of the genotype -phenotype relationship of this deafness gene and provides a sensitive and simple functional assay for missense mutations in this gene, which may assist future molecular diagnosis of autosomal-dominant hearing impairment. Finally, the present results do not indicate that mutations in ACTG1 are a frequent cause of autosomal-dominant postlingual sensorineural hearing impairment in Norway nor Denmark.

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Section: Resultsmentioning

confidence: 99%

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

et al. 2006

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“…Epilepsy has been reported previously in two patients with much larger trisomic segments [Fryns et al, 1979;Parcheta et al, 1985], sensorineural hearing loss occurred in three patients; one was found to have a de novo duplication of 17q25 [Orye and Van Bever, 1985], the other two were trisomic for the segment 17q23-qter as a result of an unbalanced translocation [Cotter and Stewart, 1990;Szego et al, 1993]. Interestingly, a locus for autosomal dominant deafness (DFNA20) has been mapped to the region 17q25 [Morell et al, 2000] and the deafness in the affected individuals could be explained by hemizygosity for the as yet unidentified DFNA20 gene. Long fingers, pes valgus, and overlapping toes have been described in one other patient who was trisomic for 17q25-qter [Bridge et al, 1985].…”

Section: Discussionmentioning

confidence: 97%

Dysmorphic features and learning disability in an adult male with pure partial trisomy 17q24‐q25 due to a terminal duplication

et al. 2002

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We describe an adult male with severe learning disability, epilepsy, and dysmorphic features. Cytogenetic studies demonstrated a terminal duplication of the long arm of chromosome 17, resulting in partial trisomy 17q24-q25. Our patient shows some of the characteristic features of the distal 17q phenotype, but in addition has more unusual features such as epilepsy, sensorineural hearing loss, and long fingers and overlapping toes. We suggest that these features occur with terminal duplications of 17q.

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“…In addition, ␤ cyto -and ␥ cyto -actin proteins are differentially localized (2-5) and posttranslationally modified (6). Finally, although dominant missense mutations in ACTB encoding ␤ cyto -actin are associated with syndromic phenotypes including severe developmental malformations and bilateral deafness (7), humans carrying a variety of dominant missense mutations in ACTG1 develop postlingual nonsyndromic progressive hearing loss (DFNA20, OMIM 604717) (8)(9)(10)(11).…”

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confidence: 99%

γ-Actin is required for cytoskeletal maintenance but not development

Belyantseva

Perrin

Sonnemann

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

164

202

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␤cyto-Actin and ␥cyto-actin are ubiquitous proteins thought to be essential building blocks of the cytoskeleton in all non-muscle cells. Despite this widely held supposition, we show that ␥cyto-actin null mice (Actg1 ؊/؊ ) are viable. However, they suffer increased mortality and show progressive hearing loss during adulthood despite compensatory up-regulation of ␤cyto-actin. The surprising viability and normal hearing of young Actg1 ؊/؊ mice means that ␤cyto-actin can likely build all essential non-muscle actin-based cytoskeletal structures including mechanosensory stereocilia of hair cells that are necessary for hearing. Although ␥cyto-actin-deficient stereocilia form normally, we found that they cannot maintain the integrity of the stereocilia actin core. In the wild-type, ␥cyto-actin localizes along the length of stereocilia but re-distributes to sites of F-actin core disruptions resulting from animal exposure to damaging noise. In Actg1 ؊/؊ stereocilia similar disruptions are observed even without noise exposure. We conclude that ␥cyto-actin is required for reinforcement and long-term stability of F-actin-based structures but is not an essential building block of the developing cytoskeleton.actin ͉ cytoskeleton ͉ hearing T here are six genes encoding six vertebrate actins that are classified according to where they are predominately expressed. ␣ skeletal -Actin, ␣ smooth -actin, ␣ cardiac -actin, and ␥ smoothactin are primarily found in muscle cells, whereas cytoplasmic ␤ cyto -actin and ␥ cyto -actin are ubiquitously and highly expressed in non-muscle cells, as reviewed elsewhere (1). Athough ␤ cytoactin and ␥ cyto -actin differ at only four biochemically similar amino acid residues in their N-termini, several lines of evidence suggest that each protein is functionally distinct. The amino acid sequences of ␤ cyto -and ␥ cyto -actin are each exactly conserved among avian and mammalian species. In addition, ␤ cyto -and ␥ cyto -actin proteins are differentially localized (2-5) and posttranslationally modified (6). Finally, although dominant missense mutations in ACTB encoding ␤ cyto -actin are associated with syndromic phenotypes including severe developmental malformations and bilateral deafness (7), humans carrying a variety of dominant missense mutations in ACTG1 develop postlingual nonsyndromic progressive hearing loss (DFNA20, OMIM 604717) (8-11).␥ cyto -Actin is widely expressed in the inner ear sensory epithelial cells on which mammalian hearing depends. These cells are organized in rows along the cochlea length: one row of inner hair cells (IHCs) and three rows of outer hair cells (OHCs) (Fig. 2A). IHCs function as auditory receptors, converting sound energy into neuronal signals, whereas OHCs enhance sensitivity to sound stimuli, as reviewed elsewhere (12). The apical surface of a hair cell is topped with actin-rich microvilli-derived protrusions termed stereocilia, which deflect in response to sound stimuli, initiating mechanoelectrical transduction (Fig. 2B). ␤ cyto -and ␥ cyto -Actin are both thou...

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A New Locus for Late-Onset, Progressive, Hereditary Hearing Loss DFNA20 Maps to 17q25

Cited by 50 publications

References 16 publications

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

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

Dysmorphic features and learning disability in an adult male with pure partial trisomy 17q24‐q25 due to a terminal duplication

γ-Actin is required for cytoskeletal maintenance but not development

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