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

Abstract

Hereditary hearing impairment is a common sensory disorder that is genetically and phenotypically heterogeneous. In this study, we used a homozygosity mapping and exome sequencing strategy to study a consanguineous Pakistani family with autosomal recessive severe-to-profound hearing impairment. This led to the identification of a missense variant (p.Ile369Thr) in the LMX1A gene affecting a conserved residue in the C-terminus of the protein, which was predicted damaging by an in silico bioinformatics analysis. The p.Ile369Thr variant disrupts several C-terminal and homeodomain residue interactions, including an interaction with homeodomain residue p.Val241 that was previously found to be involved in autosomal dominant progressive HI. LIM-homeodomain factor Lmxla is expressed in the inner ear through development, shows a progressive restriction to non-sensory epithelia, and is important in the separation of the sensory and non-sensory domains in the inner ear. Homozygous Lmxla mutant mice (Dreher) are deaf with dysmorphic ears with an abnormal morphogenesis and fused and misshapen sensory organs; however, computed tomography performed on a hearing-impaired family member did not reveal any cochleovestibular malformations. Our results suggest that LMX1A is involved in both human autosomal recessive and dominant sensorineural hearing impairment.

Single-Cell RNA Analysis of Type I Spiral Ganglion Neurons Reveals a Lmx1a Population in the Cochlea

“…Lmx1a expression has long been seen in the mammalian inner ear and cochlea. Data from human studies reported that loss of function mutations lead to deafness in human populations (Schrauwen et al, 2018;Wesdorp et al, 2018). Furthermore, mutations in Lmx1a in mice lead to the improper establishment of the sensory-non-sensory regions of the ear, leading to altered ear morphology (Koo et al, 2009).…”

Biological insights from multi-omic analysis of 31 genomic risk loci for adult hearing difficulty

“…We sought independent support for roles of these genes in hearing loss or cochlear function based on prior evidence from genetic studies in humans and mice. Rare mutations in five of the 50 genes have been shown previously to cause Mendelian forms of deafness or hearing loss: TRIOBP , EYA4 , FTO , SOX2 , and LMX1A [ 4 , 45 – 53 ]. Genetic studies in mice have demonstrated hearing loss or cochlear development phenotypes for an additional seven of the 50 genes: SYNJ2 , TYR , PTGDR , MMP2 , RPGRIP1L , RBL2 , and BAIAPL2 [ 54 – 60 ].…”

Biological insights from multi-omic analysis of 31 genomic risk loci for adult hearing difficulty

“…We sought independent support for roles of these genes in hearing loss or cochlear function based on prior evidence from genetic studies in humans and mice. Rare mutations in five of the 50 genes have been shown previously to cause Mendelian forms of deafness or hearing loss: TRIOBP, EYA4, FTO, SOX2, and LMX1A 4, [35][36][37][38][39][40][41][42][43] . Genetic studies in mice have demonstrated hearing loss or cochlear development phenotypes for an additional seven of the 50 genes: SYNJ2, TYR, PTGDR, MMP2, RPGRIP1L, RBL2, and BAIAPL2 [44][45][46][47][48][49][50] .…”