A mouse model for human hearing loss DFNB30 due to loss of function of myosin IIIA

Walsh, Vanessa; Raviv, Dorith; Dror, Amiel A.; Shahin, Hashem; Walsh, Tom; Kanaan, Moien; Avraham, Karen B.; King, Mary Claire

doi:10.1007/s00335-010-9310-6

Cited by 45 publications

(38 citation statements)

References 27 publications

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“…1 B), suggesting that OHC function was not impaired. Together, these results are consistent with late-onset, mild hearing loss in Myo3a −/− mice, reminiscent of the hearing loss in Myo3a KI/KI mice (Walsh et al, 2011). In contrast, the ABR thresholds and the DPO AE thresholds and amplitudes of Myo3b −/− mice measured between 2 and 4 mo showed no statistically significant difference compared with those of control mice (P > 0.1; Fig.…”

Section: Resultssupporting

confidence: 84%

Class III myosins shape the auditory hair bundles by limiting microvilli and stereocilia growth

Lelli¹,

Michel²,

Monvel³

et al. 2016

J Gen Physiol

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Section: Resultssupporting

confidence: 84%

Class III myosins shape the auditory hair bundles by limiting microvilli and stereocilia growth

Lelli¹,

Michel²,

Monvel³

et al. 2016

J Gen Physiol

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“…MYO3A was found to play a role in maintaining stereocilia ultrastructure as the DFNB30 mouse displays age-dependent stereocilia degeneration (12). Our working hypothesis is that the localization and activity of class III myosins play a role in transport within actin bundle protrusions.…”

Section: Discussionmentioning

confidence: 91%

“…ESPN1 contains WH2 activity, which binds actin monomers and promotes filament elongation. Disruption of the MYO3A gene is associated with nonsyndromic deafness (DFNB30) (11), and a mouse model of DFNB30 results in age-dependent degeneration of the stereocilia of inner ear hair cells (12). Therefore, characterizing mechanisms of MYO3 motor and kinase regulation are critical for understanding its role in sensory cells.…”

mentioning

confidence: 99%

Myosin 3A Kinase Activity Is Regulated by Phosphorylation of the Kinase Domain Activation Loop

Quintero

Unrath

Stevens

et al. 2013

Journal of Biological Chemistry

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Background: Class III myosins contain both a motor and kinase domain. Results: Phosphorylation of the kinase activation loop enhances MYO3A kinase activity, augmenting autophosphorylationinduced attenuation of motor and cellular activity. Conclusion: MYO3A kinase activity mediates localization and function within actin protrusions. Significance: Characterizing MYO3A kinase regulation enhances our understanding of the role of MYO3A in the maintenance of actin protrusions found in sensory epithelia.

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“…The UK10K study also suggested that reported estimates of disease variant penetrance were too high (16). These findings have increasing relevance as exome and genome sequencing move into population scale surveys for example we observed adults with a GJB2 knockout (p.Trp77Ter, a published deafness risk variant (17)) without any symptoms of hearing loss, and a MYO3A knockout without any symptoms of hearing loss and with normal audiometry (18,19).…”

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confidence: 90%

Health and population effects of rare gene knockouts in adult humans with related parents

Narasimhan

Hunt

Mason

et al. 2015

Preprint

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Abstract:Complete gene knockouts are highly informative about gene function. We exome sequenced 3,222 British Pakistani heritage adults with high parental relatedness, discovering 1,111 rare variant homozygous likely loss of function (rhLOF) genotypes predicted to disrupt (knockout) 781 genes. Based on depletion of rhLOF genotypes, we estimate that 13.6% of knockouts are incompatible with adult life, finding on average 1.6 heterozygous recessive lethal LOF variants per adult. Linking to lifelong health records, we observed no association of rhLOF genotypes with prescription or doctor consultation rate, and no disease related phenotypes in 33 of 42 individuals with rhLOF genotypes in recessive Mendelian disease genes. Phased genome sequencing of a healthy PRDM9 knockout mother, her child and controls, showed meiotic recombination sites localised away from PRDM9 dependent hotspots, demonstrating PRDM9 redundancy in humans. Main Text:The study of gene function by correlating genotype with phenotype has provided profound biological insights for several decades. In particular, complete gene knockouts, typically caused by homozygous loss of function (LOF) genotypes, have been used to identify the function of many genes, predominantly through studies in model organisms and of severe Mendelian inherited diseases in humans. However, information on the consequences of knocking out most genes in humans is still missing. Naturally occurring complete gene knockouts, whilst exceptional in outbred populations, offer the opportunity to study directly the lifelong effects of systemic gene inactivation in a living human. They provide a key entry point into human biology that can then be tested in other systems, and can lead to direct validation of specific biological hypotheses. The first large survey of LOF variants in adult humans demonstrated ~100 predicted LOF genotypes per individual, describing around ~20 genes carrying homozygous predicted LOF alleles and hence likely completely inactivated(1). As expected almost all these homozygous genotypes were common (allele frequency) variants, and were concentrated in genes likely to have weak or neutral effects on fitness and health, for instance olfactory receptors. In contrast, rare predicted LOF genotypes in these outbred . CC-BY-NC-ND 4.0 International license peer-reviewed) is the author/funder. It is made available under a The copyright holder for this preprint (which was not . http://dx.doi.org/10.1101/031641 doi: bioRxiv preprint first posted online Nov. 14, 2015; samples were usually heterozygous and thus of uncertain overall impact on gene function. Several approaches have been described recently to identify naturally occurring human knockouts. A large exome sequencing aggregation study (ExAC), of predominantly outbred individuals, identified 1,775 genes with homozygous predicted LOF genotypes in 60,706 individuals(2). In population isolates, 1,171 genes with complete predicted LOF were identified in 104,220 Icelandic individuals(3), and modest enrichment for homozygou...

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A mouse model for human hearing loss DFNB30 due to loss of function of myosin IIIA

Cited by 45 publications

References 27 publications

Class III myosins shape the auditory hair bundles by limiting microvilli and stereocilia growth

Class III myosins shape the auditory hair bundles by limiting microvilli and stereocilia growth

Myosin 3A Kinase Activity Is Regulated by Phosphorylation of the Kinase Domain Activation Loop

Health and population effects of rare gene knockouts in adult humans with related parents

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