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

Human Genetics
Mieke WesdorpHannie Kremer

Abstract

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 progre...Continue Reading

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Citations

Jan 3, 2019·Genomics & Informatics·Nathanial T Carpena, Min Young Lee
Apr 4, 2020·The Laryngoscope·Shadi AhmadmehrabiDaniel J Rader
Jul 5, 2018·Human Genetics·Isabelle SchrauwenSuzanne M Leal
Apr 28, 2020·Human Molecular Genetics·Karina LezirovitzJeanne Oiticica
Jun 12, 2020·Frontiers in Molecular Neuroscience·Fiorella Carla GrandiMirna Mustapha
Nov 3, 2020·RNA Biology·Tal Koffler-BrillKaren B Avraham
May 29, 2021·Journal of Anatomy·Kacey MackowetzkyAndrew J Waskiewicz

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Methods Mentioned

BETA
exome sequencing
genotyping
PCR
protein folding

Software Mentioned

WebLogo
GeneSplicer
- like
SpliceSiteFinder
PhyloP
NNSPLICE
Alamut Visual
Polyphen
SIFT
GnomAD

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