Novel ACTG1 mutation causing autosomal dominant non-syndromic hearing impairment in a Chinese family

doi:10.1016/S1673-8527(08)60075-2

Journal of Genetics and Genomics

Volume 35, Issue 9, September 2008, Pages 553-558

https://doi.org/10.1016/S1673-8527(08)60075-2 Get rights and content

Abstract

The γ-actin (ACTG1) gene is a cytoplasmic nonmuscle actin gene, which encodes a major cytoskeletal protein in the sensory hair cells of the cochlea. Mutations in ACTG1 were found to cause autosomal dominant, progressive, sensorineural hearing loss linked to the DFNA 20/26 locus on chromosome 17q25.3 in European and American families, respectively. In this study, a novel missense mutation (c.364A>G; p.I122V) co-segregated with the affected individuals in the family and did not exist in the unaffected family members and 150 unrelated normal controls. The alteration of residue Ile122 was predicted to damage its interaction with actin-binding proteins, which may cause disruption of hair cell organization and function. These findings strongly suggested that the I122V mutation in ACTG1 caused autosomal dominant non-syndromic hearing impairment in a Chinese family and expanded the spectrum of ACTG1 mutations causing hearing loss.

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Building and repairing the stereocilia cytoskeleton in mammalian auditory hair cells
2019, Hearing Research
Citation Excerpt :
In the absence of either the β- or γ-actin isoform, auditory hair cell stereocilia develop normally but exhibit premature stereocilia degeneration (Belyantseva et al., 2009; Patrinostro et al., 2018; Perrin et al., 2010b). In humans, mutations in β-actin are typically associated with syndromic types of hearing loss, while mutations in γ-actin cause either syndromic or non-syndromic progressive hearing loss (Liu et al., 2008; Morin et al., 2009; Procaccio et al., 2006; Rendtorff et al., 2006; Riviere et al., 2012; van Wijk et al., 2003; Zhu et al., 2003). Therefore, it is reasonable to speculate that β-actin has a major structural role in stereocilia, while γ-actin also participates in stereocilia repair.
Despite all recent achievements in identification of the molecules that are essential for the structure and mechanosensory function of stereocilia bundles in the auditory hair cells of mammalian species, we still have only a rudimentary understanding of the mechanisms of stereocilia formation, maintenance, and repair. Important molecular differences distinguishing mammalian auditory hair cells from hair cells of other types and species have been recently revealed. In addition, we are beginning to solve the puzzle of the apparent life-long stability of the stereocilia bundles in these cells. New data link the stability of the cytoskeleton in the mammalian auditory stereocilia with the normal activity of mechanotransduction channels. These data suggest new ideas on how a terminally-differentiated non-regenerating hair cell in the mammalian cochlea may repair and tune its stereocilia bundle throughout the life span of the organism.
Amino acid 118 in the deafness causing (DFNA20/26) ACTG1 gene is a mutational hot spot
2018, Gene Reports
Citation Excerpt :
Therefore, mutations that change the amino acid structure of actin are generally not tolerated. To date, a total of 18 mutations in ACTG1 gene associated with DFNA20/26 have been reported (Fig. 4) (Zhu et al., 2003; de Heer et al., 2009; Khaitlina, 2001; Morin et al., 2009; Liu et al., 2008; Baek et al., 2012; Yuan et al., 2016; Mutai et al., 2013; Miyagawa et al., 2013; Park et al., 2003; Wei et al., 2014; Vona et al., 2014; Rendtorff et al., 2006). These mutations are located in various binding domain, but so far only missense mutations have been identified.
Hearing loss is an economically and socially important cause of human morbidity, affecting 360 million people (over 5% of the world's population), of whom 32 million are children. Of the estimated minimum of 50% of hereditary hearing loss, non-syndromic hearing loss (NSHL) accounts for >70%. The autosomal dominant non-syndromic hearing loss (ADNSHL) is highly heterogeneous. To date, 67 ADNSHL loci (DFNA1-67) have been mapped; however, only approximately 35 causative genes have been cloned since 1997 (http://hereditaryhearingloss.org/).
To identify the genetic basis of hereditary hearing loss in a Chinese family with ADNSHL, we undertook a targeted sequencing of 180 genes using a custom capture panel (MiamiOtoGenes).
The onset of hearing loss in the family occurred between the ages of 15 and 18 years. Hearing loss was bilateral, started in the high frequency and progressed to lower frequencies. The c.353A > T (K118M) in the ACTG1 gene was identified by panel and was confirmed by Sanger sequencing and was present in all affected family members. So far, five of the 23 DFNA20/26 families worldwide have been found to carry mutation involving the residue K118.
This is the first report of K118M mutation in the ACTG1 gene causing hearing loss in the Chinese population. The present data are in line with previous evidence to suggest that codon K118 of ACTG1 may represent a mutational hot spot that justifies a mutation screen for diagnostic purpose in the genetically heterogeneous group of DFNA20/26.
Actin in hair cells and hearing loss
2012, Hearing Research
Citation Excerpt :
Genes in the 2.4-Mb DFNA20/26 interval were screened by DNA sequencing, and a missense mutation (p.T89I) that substitutes an isoleucine for the wild-type threonine at residue 89 of ACTG1 was found to co-segregate with deafness in this family (Zhu et al., 2003). Nine additional missense mutations of ACTG1 have been identified, each of which has been reported in just one family (van Wijk et al., 2003; Zhu et al., 2003; Rendtorff et al., 2006; Liu et al., 2008; de Heer et al., 2009; Morin et al., 2009). All ten of the DFNA20/26 ACTG1 missense mutations described to date (Fig. 1) result in a similar phenotype.
Hereditary deafness is genetically heterogeneous such that mutations of many different genes can cause hearing loss. This review focuses on the evidence and implications that several of these deafness genes encode actin-interacting proteins or actin itself. There is a growing appreciation of the contribution of the actin interactome in stereocilia development, maintenance, mechanotransduction and malfunction of the auditory system.
Drosophila indirect flight muscle specific Act88F actin mutants as a model system for studying congenital myopathies of the human ACTA1 skeletal muscle actin gene
2010, Neuromuscular Disorders
Citation Excerpt :
Currently, except for the γ-enteric actin gene (ACTG2), all other actins have been implicated in various diseases. Mutations of the human cytoplasmic γ-actin ACTG1 gene have been associated with autosomal dominant deafness [1–4]; ACTB gene (β-cytoskeletal actin) with neutrophil dysfunction, recurrent infection, developmental malformations, deafness and dystonia [5,6] and ACTA2 gene (smooth muscle α-actin) with thoracic aortic aneurysms and dissections, coronary artery disease, stroke and Moyamoya disease [7,8]. Cardiac actin gene, ACTC, mutations cause dilated [9] or hypertrophic cardiomyopathies [10–13].
Most human ACTA1 skeletal actin gene mutations cause dominant, congenital myopathies often with severely reduced muscle function and neonatal mortality. High sequence conservation of actin means many mutated ACTA1 residues are identical to those in the Drosophila Act88F, an indirect flight muscle specific sarcomeric actin. Four known Act88F mutations occur at the same actin residues mutated in ten ACTA1 nemaline mutations, A138D/P, R256H/L, G268C/D/R/S and R372C/S. These Act88F mutants were examined for similar muscle phenotypes. Mutant homozygotes show phenotypes ranging from a lack of myofibrils to almost normal sarcomeres at eclosion. Aberrant Z-disc-like structures and serial Z-disc arrays, ‘zebra bodies’, are observed in homozygotes and heterozygotes of all four Act88F mutants. These electron-dense structures show homologies to human nemaline bodies/rods, but are much smaller than those typically found in the human myopathy. We conclude that the Drosophila indirect flight muscles provide a good model system for studying ACTA1 mutations.
Hearing Loss in Baraitser–Winter Syndrome: Case Reports and Review of the Literature
2024, Journal of Clinical Medicine
Autosomal Dominant Non-Syndromic Hearing Loss (DFNA): A Comprehensive Narrative Review
2023, Biomedicines

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¹: These authors contributed equally to this work.

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Abstract

References (15)

Effects of human deafness γ-actin mutations (DFNA20/26) on actin function

J. Biol. Chem.

Localization of a calcium sensitive binding site for gelsolin on actin subdomain I: Implication for severing process

Biochem. Biophys. Res. Commun.

Functional specificity of actin isoforms

Int. Rev. Cytology.

SCN5A mutations associated with an inherited cardiac arrhythmia, long QT syndrome

Cell

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

Am. J. Hum. Genet.

Hereditary deafness and phenotyping in humans

Br. Med. Bull.

The structure of the cuticular plate, an in vivo actin gel

J. Cell Biol.

Cited by (26)

Building and repairing the stereocilia cytoskeleton in mammalian auditory hair cells

Amino acid 118 in the deafness causing (DFNA20/26) ACTG1 gene is a mutational hot spot

Actin in hair cells and hearing loss

Drosophila indirect flight muscle specific Act88F actin mutants as a model system for studying congenital myopathies of the human ACTA1 skeletal muscle actin gene

Hearing Loss in Baraitser–Winter Syndrome: Case Reports and Review of the Literature

Autosomal Dominant Non-Syndromic Hearing Loss (DFNA): A Comprehensive Narrative Review