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. 2018 May;137(5):389-400.
doi: 10.1007/s00439-018-1880-5. Epub 2018 May 12.

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

Mieke Wesdorp  1   2   3 , Pia A M de Koning Gans  4 , Margit Schraders  1   3 , Jaap Oostrik  1   3 , Martijn A Huynen  5 , Hanka Venselaar  5 , Andy J Beynon  1 , Judith van Gaalen  3   6 , Vitória Piai  3   7 , Nicol Voermans  3   6 , Michelle M van Rossum  8 , Bas P Hartel  1   3 , Stefan H Lelieveld  2   9 , Laurens Wiel  2   4   9 , Berit Verbist  10   11 , Liselotte J Rotteveel  12 , Marieke F van Dooren  13 , Peter Lichtner  14 , Henricus P M Kunst  1 , Ilse Feenstra  9 , Ronald J C Admiraal  1 ; DOOFNL Consortium; Helger G Yntema  3   9 , Lies H Hoefsloot  13 , Ronald J E Pennings  1   3 , Hannie Kremer  15   16   17
Collaborators, Affiliations

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

Mieke Wesdorp et al. Hum Genet. 2018 May.

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.

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Conflict of interest statement

The authors have no conflict of interest to declare.

Figures

Fig. 1
Fig. 1
Pedigrees, VNTR genotypes and segregation of LMX1A variants. a Genotypes of VNTR markers and segregation of the identified missense variant of LMX1A in family W15-0551. Genetic locations of the markers were derived online from the Marshfield genetic map and maker order was confirmed in the human genome assembly GRCh37/hg19. As the variant resides on an allele (depicted in red) that is shared by non-affected siblings of subject II:7, the variant was concluded to be de novo in subject II:7. It remained unclear whether subject I:2 was affected only at high age or earlier, based on conflicting subjective information provided by her family members. b Pedigree and segregation analyses of a missense variant in LMX1A in family 63136. Index cases are indicated by arrows. + Wild type (color figure online)
Fig. 2
Fig. 2
Domains and conservation of (mutated) residues in the LIM-homeodomain protein family. The presented conservation of the second LIM domain and the homeodomain shows that the mutated residues Cys97 and Val241 (indicated by arrows) are perfectly conserved. Within the second LIM domain, the residues that together bind two zinc atoms are indicated with black lines above the amino acid sequence
Fig. 3
Fig. 3
Audiometric characterization of families affected by deleterious LMX1A variants. Air conduction thresholds of both ears of the affected individuals are shown of first-visit and last-visit audiometry. The 95th percentile threshold values of presbyacusis (p95) were calculated for the last-visit audiogram, and matched to the individual’s sex and age, according to the ISO 7029 standard. a Family W15-0551. For subject II:7, also bone conduction thresholds of the left ear are depicted, because of mixed HI due to fenestral otosclerosis (conductive HI) and the LMX1A variant (sensorineural HI). b Family 63136. Subjects did not participate in our clinical evaluation; only retrospective data were used for analysis. R right ear, L left ear
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