Heterozygous missense variants of LMX1A lead to nonsyndromic hearing impairment and vestibular dysfunction
Number of pages
SourceHuman Genetics, 137, 5, (2018), pp. 389-400
Article / Letter to editor
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SW OZ DCC NRP
Radiology & Nuclear Medicine
SubjectAll institutes and research themes of the Radboud University Medical Center; DI-BCB_DCC_Theme 3: Plasticity and Memory; Neuropsychology and rehabilitation psychology; Radboudumc 12: Sensory disorders DCMN: Donders Center for Medical Neuroscience; Radboudumc 19: Nanomedicine RIMLS: Radboud Institute for Molecular Life Sciences; Radboudumc 2: Cancer development and immune defence RIHS: Radboud Institute for Health Sciences; Radboudumc 3: Disorders of movement DCMN: Donders Center for Medical Neuroscience; Radboudumc 6: Mitochondrial diseases RIMLS: Radboud Institute for Molecular Life Sciences; Radboudumc 7: Neurodevelopmental disorders DCMN: Donders Center for Medical Neuroscience; Radboudumc 9: Rare cancers RIHS: Radboud Institute for Health Sciences; Radboudumc 6: Metabolic Disorders RIMLS: Radboud Institute for Molecular Life Sciences; Neuro- en revalidatiepsychologie; Radboudumc 6: Mitochondrial diseases RIMLS: Radboud Institute for Molecular Life Sciences; Radboudumc 6: Metabolic Disorders RIMLS: Radboud Institute for Molecular Life Sciences
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.
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