A genotypic ascertainment approach to refute the association of MYO1A variants with non-syndromic deafness

Patton, John H; Brewer, Carmen C.; Johnston, Jennifer J.; Griffith, Andrew J.; Biesecker, Leslie G.

doi:10.1038/ejhg.2016.140

Cited by 11 publications

(6 citation statements)

References 15 publications

(17 reference statements)

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“…However, we need to beware of seemingly causative variants that segregate in small families or occur in several unique individuals with hearing impairment (HI) by coincidence, especially in dominant NSHI. This is illustrated by the recent disqualification of MYO1A (MIM: 601478) as a deafness gene (Eisenberger et al 2014 ; Patton et al 2016 ). Ideally, unique pathogenic variants are identified in several families with a similar phenotype and not in a significant number of controls.…”

Section: Introductionmentioning

confidence: 99%

Heterozygous missense variants of LMX1A lead to nonsyndromic hearing impairment and vestibular dysfunction

et al. 2018

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Unraveling the causes and pathomechanisms of progressive disorders is essential for the development of therapeutic strategies. Here, we identified heterozygous pathogenic missense variants of LMX1A in two families of Dutch origin with progressive nonsyndromic hearing impairment (HI), using whole exome sequencing. One variant, c.721G > C (p.Val241Leu), occurred de novo and is predicted to affect the homeodomain of LMX1A, which is essential for DNA binding. The second variant, c.290G > C (p.Cys97Ser), predicted to affect a zinc-binding residue of the second LIM domain that is involved in protein–protein interactions. Bi-allelic deleterious variants of Lmx1a are associated with a complex phenotype in mice, including deafness and vestibular defects, due to arrest of inner ear development. Although Lmx1a mouse mutants demonstrate neurological, skeletal, pigmentation and reproductive system abnormalities, no syndromic features were present in the participating subjects of either family. LMX1A has previously been suggested as a candidate gene for intellectual disability, but our data do not support this, as affected subjects displayed normal cognition. Large variability was observed in the age of onset (a)symmetry, severity and progression rate of HI. About half of the affected individuals displayed vestibular dysfunction and experienced symptoms thereof. The late-onset progressive phenotype and the absence of cochleovestibular malformations on computed tomography scans indicate that heterozygous defects of LMX1A do not result in severe developmental abnormalities in humans. We propose that a single LMX1A wild-type copy is sufficient for normal development but insufficient for maintenance of cochleovestibular function. Alternatively, minor cochleovestibular developmental abnormalities could eventually lead to the progressive phenotype seen in the families.Electronic supplementary materialThe online version of this article (10.1007/s00439-018-1880-5) contains supplementary material, which is available to authorized users.

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Section: Introductionmentioning

confidence: 99%

Heterozygous missense variants of LMX1A lead to nonsyndromic hearing impairment and vestibular dysfunction

et al. 2018

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“…To date, three genes encoding the class-I myosins, MYO1A , MYO1C and MYO1F , were initially reported as human “deafness genes” ( Donaudy et al, 2003 ; Zadro et al, 2009 ). Association of variants of MYO1A with deafness was refuted as either the variants of MYO1A were identified in healthy controls or the deafness was explained by convincing variants of different genes ( Eisenberger et al, 2014 ; Patton et al, 2016 ). Absence of any overt pathology in homozygous Myo1a knockout mice supports these findings ( Tyska et al, 2005 ).…”

Section: Myosins and Hearing Lossmentioning

confidence: 99%

Pathophysiology of human hearing loss associated with variants in myosins

Miyoshi,

Belyantseva,

Sajeevadathan

et al. 2024

Front. Physiol.

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Deleterious variants of more than one hundred genes are associated with hearing loss including MYO3A, MYO6, MYO7A and MYO15A and two conventional myosins MYH9 and MYH14. Variants of MYO7A also manifest as Usher syndrome associated with dysfunction of the retina and vestibule as well as hearing loss. While the functions of MYH9 and MYH14 in the inner ear are debated, MYO3A, MYO6, MYO7A and MYO15A are expressed in inner ear hair cells along with class-I myosin MYO1C and are essential for developing and maintaining functional stereocilia on the apical surface of hair cells. Stereocilia are large, cylindrical, actin-rich protrusions functioning as biological mechanosensors to detect sound, acceleration and posture. The rigidity of stereocilia is sustained by highly crosslinked unidirectionally-oriented F-actin, which also provides a scaffold for various proteins including unconventional myosins and their cargo. Typical myosin molecules consist of an ATPase head motor domain to transmit forces to F-actin, a neck containing IQ-motifs that bind regulatory light chains and a tail region with motifs recognizing partners. Instead of long coiled-coil domains characterizing conventional myosins, the tails of unconventional myosins have various motifs to anchor or transport proteins and phospholipids along the F-actin core of a stereocilium. For these myosins, decades of studies have elucidated their biochemical properties, interacting partners in hair cells and variants associated with hearing loss. However, less is known about how myosins traffic in a stereocilium using their motor function, and how each variant correlates with a clinical condition including the severity and onset of hearing loss, mode of inheritance and presence of symptoms other than hearing loss. Here, we cover the domain structures and functions of myosins associated with hearing loss together with advances, open questions about trafficking of myosins in stereocilia and correlations between hundreds of variants in myosins annotated in ClinVar and the corresponding deafness phenotypes.

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“…Two class I myosins have been described to play potential roles in the hearing process, MYO1A and MYO1C. Although originally found expressed in the inner ear, MYO1A was later ruled out as a candidate hearing loss gene ( Patton et al, 2016 ). Therefore, much research has focused on MYO1C as the predominant hearing-associated class I myosin ( Adamek et al, 2011 ; Lin et al, 2011 ; Pyrpassopoulos et al, 2012 ).…”

Section: The Myosin Superfamilymentioning

confidence: 99%

Functional Role of Class III Myosins in Hair Cells

Cirilo

Gunther

Yengo

2021

Front. Cell Dev. Biol.

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Cytoskeletal motors produce force and motion using the energy from ATP hydrolysis and function in a variety of mechanical roles in cells including muscle contraction, cargo transport, and cell division. Actin-based myosin motors have been shown to play crucial roles in the development and function of the stereocilia of auditory and vestibular inner ear hair cells. Hair cells can contain hundreds of stereocilia, which rely on myosin motors to elongate, organize, and stabilize their structure. Mutations in many stereocilia-associated myosins have been shown to cause hearing loss in both humans and animal models suggesting that each myosin isoform has a specific function in these unique parallel actin bundle-based protrusions. Here we review what is known about the classes of myosins that function in the stereocilia, with a special focus on class III myosins that harbor point mutations associated with delayed onset hearing loss. Much has been learned about the role of the two class III myosin isoforms, MYO3A and MYO3B, in maintaining the precise stereocilia lengths required for normal hearing. We propose a model for how class III myosins play a key role in regulating stereocilia lengths and demonstrate how their motor and regulatory properties are particularly well suited for this function. We conclude that ongoing studies on class III myosins and other stereocilia-associated myosins are extremely important and may lead to novel therapeutic strategies for the treatment of hearing loss due to stereocilia degeneration.

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A genotypic ascertainment approach to refute the association of MYO1A variants with non-syndromic deafness

Cited by 11 publications

References 15 publications

Heterozygous missense variants of LMX1A lead to nonsyndromic hearing impairment and vestibular dysfunction

Heterozygous missense variants of LMX1A lead to nonsyndromic hearing impairment and vestibular dysfunction

Pathophysiology of human hearing loss associated with variants in myosins

Functional Role of Class III Myosins in Hair Cells

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