Nonsyndromic hearing impairment is associated with a mutation in DFNA5

Laer, Lut Van; Huizing, Egbert H.; Verstreken, M.; Zuijlen, Diederick van; Wauters, J.; Bossuyt, P.; Heyning, Paul Van de; McGuirt, Wyman T.; Smith, Richard J.H.; Willems, Patrick J.; Legan, P. Kevin; Richardson, Guy P.; Camp, Guy Van

doi:10.1038/2503

Cited by 324 publications

(131 citation statements)

References 18 publications

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“…2). Nevertheless, genetic mutations within intron 7 of human DFNA5 that cause skipping of exon 8 and truncation of the C-terminus of DFNA5 at residue 315 leads to hearing loss21, suggesting that the N-terminal domain of DFNA5, like GSDMD N-terminal domain, may possess cell-death inducing activity. As a first step to investigate whether DFNA5 is an effector of necrotic-like cell death downstream of caspase activation, we tested whether DFNA5 is a target for caspases.…”

Section: Resultsmentioning

confidence: 99%

“…All DFNA5 mutations leading to hearing loss in humans have been attributed to exon 8 skipping at the pre-mRNA level leading to the translation of a C-terminally truncated DFNA5 protein2151. Because ectopic expression of this mutant protein cause cell death, it has been proposed that the DFNA5 mutations represent gain of function mutations that increase the apoptotic activity of DFNA5 (ref.…”

Section: Discussionmentioning

confidence: 99%

“…Mutations in intron 7 of the DFNA5 gene have been shown to cause sensorineural hearing loss because of skipping of exon 8 at the pre-mRNA level and the translation of a C-terminally truncated protein2021. Although the full-length product does not have cytotoxic activity, the truncated form does1819.…”

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confidence: 99%

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Cleavage of DFNA5 by caspase-3 during apoptosis mediates progression to secondary necrotic/pyroptotic cell death

et al. 2017

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Apoptosis is a genetically regulated cell suicide programme mediated by activation of the effector caspases 3, 6 and 7. If apoptotic cells are not scavenged, they progress to a lytic and inflammatory phase called secondary necrosis. The mechanism by which this occurs is unknown. Here we show that caspase-3 cleaves the GSDMD-related protein DFNA5 after Asp270 to generate a necrotic DFNA5-N fragment that targets the plasma membrane to induce secondary necrosis/pyroptosis. Cells that express DFNA5 progress to secondary necrosis, when stimulated with apoptotic triggers such as etoposide or vesicular stomatitis virus infection, but disassemble into small apoptotic bodies when DFNA5 is deleted. Our findings identify DFNA5 as a central molecule that regulates apoptotic cell disassembly and progression to secondary necrosis, and provide a molecular mechanism for secondary necrosis. Because DFNA5-induced secondary necrosis and GSDMD-induced pyroptosis are dependent on caspase activation, we propose that they are forms of programmed necrosis.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Cleavage of DFNA5 by caspase-3 during apoptosis mediates progression to secondary necrotic/pyroptotic cell death

et al. 2017

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“…All four mutations segregated with late-onset non-syndromic hearing impairment in the families. 88–90 Among the mutations identified, a CTT deletion in the polypyrimidine tract of intron 7 and an IVS8+4A-G transition in the splice-donor site of intron 8 have been described in Chinese families with non-syndromic deafness, indicating that mutations in DFNA5 may be major known causes of hereditary hearing loss in Chinese patients. 89 A truncating mutation, c.640insC, in exon 5 of DFNA5 was recently reported in an Iranian family.…”

Section: Introductionmentioning

confidence: 99%

The genetic bases for non-syndromic hearing loss among Chinese

et al. 2009

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Deafness is an etiologically heterogeneous trait with many known genetic, environmental causes or a combination thereof. The identification of more than 120 independent genes for deafness has provided profound new insights into the pathophysiology of hearing. However, recent findings indicate that a large proportion of both syndromic and non-syndromic forms of deafness in the Chinese population are caused by defects in a small number of genes. Studies of the genetic epidemiology and molecular genetic features revealed that there is a clear relevance of genes causing deafness in Chinese deaf patients as well as a unique spectrum of common and rare deafness gene mutations in the Chinese population. This review is focused on the genetic aspects of non-syndromic and mitochondrial deafness, in which unique molecular genetic features of hearing impairment have been identified in the Chinese population. The current China population is approximately 1.3 billion. It is estimated that 30 000 infants are born with congenital sensorineural hearing loss each year. Better understanding of the genetic causes of deafness in the Chinese population is important for accurate genetics counseling and early diagnosis for timely intervention and treatment options.

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“…DFNA5 was originally discovered in a Dutch family with autosomal dominant nonsyndromic hearing impairment [19]. The auditory feature of DFNA5 closely resembles that of the most frequent type of ARHI, namely, sensorineural progressive loss that begins in the high frequencies.…”

Section: Genes Causing Monogenic Hearing Impairment With Phenotypimentioning

confidence: 99%

Progress and Prospects in Human Genetic Research into Age-Related Hearing Impairment

Uchida

Sugiura

Nakashima

2014

BioMed Research International

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Age-related hearing impairment (ARHI) is a complex, multifactorial disorder that is attributable to confounding intrinsic and extrinsic factors. The degree of impairment shows substantial variation between individuals, as is also observed in the senescence of other functions. This individual variation would seem to refute the stereotypical view that hearing deterioration with age is inevitable and may indicate that there is ample scope for preventive intervention. Genetic predisposition could account for a sizable proportion of interindividual variation. Over the past decade or so, tremendous progress has been made through research into the genetics of various forms of hearing impairment, including ARHI and our knowledge of the complex mechanisms of auditory function has increased substantially. Here, we give an overview of recent investigations aimed at identifying the genetic risk factors involved in ARHI and of what we currently know about its pathophysiology. This review is divided into the following sections: (i) genes causing monogenic hearing impairment with phenotypic similarities to ARHI; (ii) genes involved in oxidative stress, biologic stress responses, and mitochondrial dysfunction; and (iii) candidate genes for senescence, other geriatric diseases, and neurodegeneration. Progress and prospects in genetic research are discussed.

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Nonsyndromic hearing impairment is associated with a mutation in DFNA5

Cited by 324 publications

References 18 publications

Cleavage of DFNA5 by caspase-3 during apoptosis mediates progression to secondary necrotic/pyroptotic cell death

Cleavage of DFNA5 by caspase-3 during apoptosis mediates progression to secondary necrotic/pyroptotic cell death

The genetic bases for non-syndromic hearing loss among Chinese

Progress and Prospects in Human Genetic Research into Age-Related Hearing Impairment

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