Modifier controls severity of a novel dominant low-frequency MyosinVIIA (MYO7A) auditory mutation

Street, Valerie A.

doi:10.1136/jmg.2003.013557

Cited by 30 publications

(32 citation statements)

References 51 publications

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“…This explanation for the dominancy of Ala230Val appears not likely since missense mutations (22 mutations identifi ed so far in the motor domain of myosin VIIA) are recessive, the only two exceptions being Asn458Ile and Gly722Arg [Street et al, 2004;Luijendijk et al, 2004]. This suggests that if a large domain, such as the motor domain of myosin VIIA, is unfolded, the entire protein is unstable.…”

Section: Discussionmentioning

confidence: 99%

“…In mammals the unconventional MYO7A gene is expressed in a variety of organs and tissues [Wolfrum et al, 1998;Sahly et al, 1997;Chen et al, 1996], but mutations in MYO7A result in altered activity within only few particular tissues of the inner ear and the eye [Adato et al, 2004;Liu et al, 1999Liu et al, , 1998Self et al, 1998]. Several proteins have been shown to interact with it [Street et al, 2004;El-Amraoui et al, 2002;Kussel-Andermann et al, 2000a, b], but given that there are no obvious clinical features, other than audiological, distinguishing the carriers of the Ala230Val indicates that other (genetic or environmental) factors may be decisive in determining the events leadings to hearing loss in our family. Experiments are now being conducted to examine the infl uence of the Ala230Val mutation on myosin VIIA function and interactions with further proteins.…”

Section: Discussionmentioning

confidence: 99%

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Identification of a Novel Mutation in the Myosin VIIA Motor Domain in a Family with Autosomal Dominant Hearing Loss (DFNA11)

Leva

D’Adamo²,

Cubellis

et al. 2006

Audiol Neurotol

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We ascertained a large Italian family with an autosomal dominant form of non-syndromic sensorineural hearing loss with vestibular involvement. A genome-wide scan found linkage to locus DFNA11. Sequencing of the MYO7A gene in the linked region identified a new missense mutation resulting in an Ala230Val change in the motor domain of the myosin VIIA. Myosin VIIA has already been implicated in several forms of deafness, but this is the third mutation causing a dominant form of deafness, located in the myosin VIIA motor domain in a region never involved in hearing loss until now. A modelled protein structure of myosin VII motor domain provides evidence for a significant functional effect of this missense mutation.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Identification of a Novel Mutation in the Myosin VIIA Motor Domain in a Family with Autosomal Dominant Hearing Loss (DFNA11)

Leva

D’Adamo²,

Cubellis

et al. 2006

Audiol Neurotol

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“…9,10 A total of 340 different mutations and 248 protein variants in MYO7A have been reported to date (http:// www.umd.be/MYO7A/). Only five MYO7A mutations leading to DFNA11 have been reported: p.delA886-K887-K888 in a Japanese pedigree, 7,11 p.G772R in an American pedigree, 12 p.N458I in a Dutch pedigree, 13 p.R853C in a German pedigree 14 and p.A230V in an Italian pedigree. 15 Here, we present the clinical, genetic and molecular characteristics of two large Chinese families with either non-syndromic high-or low-frequency DFNA11.…”

Section: Introductionmentioning

confidence: 99%

Novel missense mutations in MYO7A underlying postlingual high- or low-frequency non-syndromic hearing impairment in two large families from China

et al. 2010

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The myosin VIIA (MYO7A) gene encodes a protein classified as an unconventional myosin. Mutations within MYO7A can lead to both syndromic and non-syndromic hearing impairment in humans. Among different mutations reported in MYO7A, only five led to non-syndromic sensorineural deafness autosomal dominant type 11 (DFNA11). Here, we present the clinical, genetic and molecular characteristics of two large Chinese DFNA11 families with either high-or low-frequency hearing loss. Affected individuals of family DX-J033 have a sloping audiogram at young ages with high frequency are most affected. With increasing age, all test frequencies are affected. Affected members of family HB-S037 present with an ascending audiogram affecting low frequencies at young ages, and then all frequencies are involved with increasing age. Genome-wide linkage analysis mapped the disease loci within the DFNA11 interval in both families. DNA sequencing of MYO7A revealed two novel nucleotide variations, c.652G4A (p.D218N) and c.2011G4A (p.G671S), in the two families. It is for the first time that the mutations identified in MYO7A in the present study are being implicated in DFNA11 in a Chinese population. For the first time, we tested electrocochleography (ECochG) in a DFNA11 family with low-frequency hearing loss. We speculate that the low-frequency sensorineural hearing loss in this DFNA11 family was not associated with endolymphatic hydrops.

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Section: Genetic Modifiers Of Hearing Loss In Human Disordersmentioning

confidence: 99%

“…There is suggestive evidence that the TFB1M gene on Chr 6, which is involved in mitochondrial RNA metabolism, may be another nuclear modifier of the mitochondrial A1555G mutation, suggesting that modification of 12s rRNA is a carefully regulated process (Bykhovskaya et al, 2004). In a large American family, severity of MYO7A-associated hearing loss varied in an apparent homomorphic environment, suggesting the effect of genetic modifier(s) (Street et al, 2004).A genetic interaction between alleles of CDH23 and ATP2B2, similar to the Cdh23 mdfwAtp2b2 dfw-2J paradigm in the mouse, was recently described in a human pedigree (Schultz et al, 2005). In this family, affected members expressed variable degrees of hearing loss differentially affecting the higher frequencies.…”

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confidence: 99%

Strain background effects and genetic modifiers of hearing in mice

2006

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Genetic modifiers can be detected in mice by looking for strain background differences in inheritance or phenotype of a mutation. They can be mapped by analyses of appropriate linkage crosses and congenic lines, and modifier genes of large effect can be identified by positionalcandidate gene testing. Inbred strains of mice vary widely in onset and severity of age-related hearing loss (AHL), an important consideration when assessing hearing in mutant mice. At least 8 mapped loci and a mitochondrial variant (mt-Tr) are known to contribute to AHL in mouse strains; one locus (ahl) has been identified as a variant of the cadherin 23 gene (Cdh23 753A/G ). This variant also was shown to modify hearing loss associated with the Atp2b2 dfw-2J and Mass1 frings mutations. The hearing modifier (Moth1) of tubby (Tub tub ) mutant mice was shown to be a strain variant of the Mtap1a gene. Human hearing modifiers include DFNM1, which suppresses recessive deafness DFNB26, and a nuclear gene that modulates the severity of hearing loss associated with a mitochondrial mutation. Recently, a variant of the human ATP2B2 gene was shown to exacerbate hearing loss in individuals homozygous for a CDH23 mutation, similar to the Atp2b2 dfw-2J -Cdh23 753A/G interaction affecting hearing in mice. Because modifier genes and digenic inheritance are not always distinguishable, we also include in this review several examples of digenic inheritance of hearing loss that have been reported in both mice and humans. KeywordsModifier gene; Genetic background; Inbred mouse strain; Age-related hearing loss; Digenic inheritance; AHL; QTL Phenotypic diversity, strain background, and modifier genesGenetic modifiers are heritable factors capable of modifying the phenotype of a mutant gene without having an obvious effect on the normal condition. Modifier genes are found in all genetically mixed populations and their collective influence on a mutant phenotype is referred to as the genetic background effect or, in the case of inbred strains of mice, the strain background effect. Previously published review papers are replete with examples of the effects of modifier genes on the phenotypic diversity of a wide variety of genetic disorders in humans and mice (Barthold, 2004;Erickson, 1996;Houlston and Tomlinson, 1998;Montagutelli, 2000;Nadeau, 2001Nadeau, , 2003Romeo and McKusick, 1994;Slavotinek and Biesecker, 2003). Examples of modifier genes are especially prevalent in genetically heterogeneous phenotypes like sensorineural deafness (Slavotinek and Biesecker, 2003), and *Corresponding author. Fax: +1 207 288 6149. krj@jax.org (K.R. Johnson). NIH Public Access NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript some reviews have focused specifically on modifiers of hearing (Ahituv and Avraham, 2002;Friedman et al., 2000;Haider et al., 2002;Riazuddin et al., 2002). Here, we present an updated review on strain background effects and genetic modifiers of hearing in mice including some related results from studies of human populations.G...

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Modifier controls severity of a novel dominant low-frequency MyosinVIIA (MYO7A) auditory mutation

Cited by 30 publications

References 51 publications

Identification of a Novel Mutation in the Myosin VIIA Motor Domain in a Family with Autosomal Dominant Hearing Loss (DFNA11)

Identification of a Novel Mutation in the Myosin VIIA Motor Domain in a Family with Autosomal Dominant Hearing Loss (DFNA11)

Novel missense mutations in MYO7A underlying postlingual high- or low-frequency non-syndromic hearing impairment in two large families from China

Strain background effects and genetic modifiers of hearing in mice

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