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 Lmx1a 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 Lmx1a 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.

Keywords: Autosomal recessive hearing impairment; Deafness; Exome sequencing; LMX1A.

Fig. 1

Pedigree drawing of family 4755, audiograms for the affected family members, and p.Ile369 residue conservation. a Pedigree of family 4755 with segregation of the c.1106T>C:p.Ile369Thr variant in LMX1A. b Pure-tone audiometry audiograms for affected family members IV:1 (top; age 12) and IV:2 (bottom; age 15); x represents the results for the left ear and o for the right ear. Audiograms show a severe-to-profound hearing impairment with a slight slope with the higher frequencies affected more severely. c Conservation of the C-terminal LMX1A domain and p.Ile369 residue (arrow) amongst species and closest human paralog LMX1B. The p.Ile369 residue is highly conserved across species and human paralog LMX1B. green = high conservation; grey = medium conservation

Fig. 2

a Schematic representation of the LMX1A protein, which contains two LIM domains and one homeodomain. All reported variants in human HI are indicated on the figure. Autosomal dominant variants causing HI (p.Cys97Ser and p.Val241Leu) were reported in Wesdorp et al. 2018. The variant causing autosomal recessive HI is p.Ile369Thr. Domains were represented as described in the Universal Protein Resource (UniProt) database (Bateman et al. 2017). b Predicted three-dimensional structure of LMX1A. The variant position at residue 369 is highlighted by a box and the three domains are indicated in the same color as the schematic representation in A. c, d Close-up view of wild-type p.Ile369 (c) and mutant p.Thr369 (d) LMX1A. The residue at position 369(**) is represented by a ball-and-stick model, while the nearby residues are represented by a stick model. The hydrophobic interactions with amino acids in the homeodomain seen in the wild-type protein are lost when the threonine, polar side chain is introduced into the loop region. One of these interactions is with the residue (p.Val241*) of the previously reported autosomal dominant HI