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

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 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.

A variant in LMX1A causes autosomal recessive severe-to-profound hearing impairment

“…Interestingly, one of these interactions is with homeodomain residue (p.Val241), which was previously reported to result in autosomal dominant progressive HI (Fig. 2) (Wesdorp et al 2018). The equivalent homeodomain residue in paralog LMX1B (p.Val265Leu) is known to cause nail-patella syndrome (Dunston et al 2004; Wesdorp et al 2018).…”

“…The APC gene is involved in various forms of cancer (hereditary and somatic) (Aoki and Taketo 2007), and when tested using Sanger sequencing, it did not segregate with the phenotype. The LMX1A gene was of interest as it had previously been implicated in a mouse autosomal recessive deafness phenotype (Koo et al 2009), and very recently, it has been described in human autosomal dominant hearing impairment (Wesdorp et al 2018). The missense variant in LMX1A [dbSNP:rs763320093; NM_001174069:c.1106T>C:p.Ile-369Thr], present in the 1q23.3-24.2 homozygous region, using Sanger sequencing, was found to segregate with HI (Fig.…”

“…Dominant LMX1A variants causing non-syndromic dominant HI impact either the homeodo-main or LIM domains (Wesdorp et al 2018). The variable and progressive HI seen in these cases is believed to be due to insufficient maintenance of cochleovestibular function by one copy of LMX1A (Wesdorp et al 2018). We show that an in silico predicted damaging autosomal recessive variant in the conserved C-terminal region of LMX1A causes a pre-lingual severe-to-profound HI profile (Figs.…”

“…Recently, LMX1A was identified as a novel gene implicated in autosomal dominant progressive HI with variable age of onset, (a)symmetry, severity and progression rate, and vestibular dysfunction in half of the affected individuals (Wesdorp et al 2018). LIM homeobox transcription factor 1 alpha is a transcription factor important for neural progenitor specification and dopamine neurogenesis (Hedlund et al 2016).…”

“…The variants causing autosomal dominant HI either affected LMX1A’s homeodomain (p.Val241Leu), which is essential for DNA-binding, or one of the LIM domains (p.Cys97Ser) that are involved in protein-protein interactions (Fig. 1a) (Wesdorp et al 2018). …”