TY - JOUR
T1 - Heterozygous missense variants of LMX1A lead to nonsyndromic hearing impairment and vestibular dysfunction
AU - Wesdorp, Mieke
AU - de Koning Gans, Pia A.M.
AU - Schraders, Margit
AU - Oostrik, Jaap
AU - Huynen, Martijn A.
AU - Venselaar, Hanka
AU - Beynon, Andy J.
AU - van Gaalen, Judith
AU - Piai, Vitória
AU - Voermans, Nicol
AU - van Rossum, Michelle M.
AU - Hartel, Bas P.
AU - Lelieveld, Stefan H.
AU - Wiel, Laurens
AU - Verbist, Berit
AU - Rotteveel, Liselotte J.
AU - van Dooren, M. F.
AU - Lichtner, Peter
AU - Kunst, H. P.M.
AU - Feenstra, I.
AU - Admiraal, Ronald J.C.
AU - van Dooren, M. F.
AU - de Gier, H. H.W.
AU - Hoefsloot, E. H.
AU - van der Schroeff, M. P.
AU - Kant, S. G.
AU - Rotteveel, L. J.C.
AU - Frints, S. G.M.
AU - Hof, J. R.
AU - Stokroos, R. J.
AU - Vanhoutte, E. K.
AU - Feenstra, I.
AU - Kremer, H.
AU - Kunst, H. P.M.
AU - Pennings, Ronald J.E.
AU - Yntema, Helger G.
AU - van Essen, A. J.
AU - Free, R. H.
AU - Klein-Wassink, J. S.
AU - Yntema, Helger G.
AU - Hoefsloot, Lies H.
AU - Pennings, Ronald J.E.
AU - Kremer, Hannie
N1 - Funding Information:
Acknowledgements We are grateful to the participating subjects and their families. We thank Laura Tomas Roca for her contribution to the WES analysis. This work was financially supported by a Grant from the Heinsius Houbolt Foundation (to H. K., R. J. E. P. and H. P. M. K.). The DOOFNL consortium consists of M.F. van Dooren, H.H.W. de Gier, E.H. Hoefsloot, M.P. van der Schroeff (ErasmusMC, Rotterdam, The Netherlands), S.G. Kant, L.J.C. Rotteveel (LUMC, Leiden, The Netherlands), S.G.M. Frints, J.R. Hof, R.J. Stokroos, E.K. Vanhoutte (MUMC+, Maastricht, The Netherlands), R.J.C. Admiraal, I. Feenstra, H. Kremer, H.P.M. Kunst, R.J.E. Pennings, H.G. Yntema (Radbou-dumc, Nijmegen, The Netherlands) A.J. van Essen, R.H. Free and J.S. Klein-Wassink (UMCG, Groningen, The Netherlands).
Funding Information:
We are grateful to the participating subjects and their families. We thank Laura Tomas Roca for her contribution to the WES analysis. This work was financially supported by a Grant from the Heinsius Houbolt Foundation (to H. K., R. J. E. P. and H. P. M. K.). The DOOFNL consortium consists of M.F. van Dooren, H.H.W. de Gier, E.H. Hoefsloot, M.P. van der Schroeff (ErasmusMC, Rotterdam, The Netherlands), S.G. Kant, L.J.C. Rotteveel (LUMC, Leiden, The Netherlands), S.G.M. Frints, J.R. Hof, R.J. Stokroos, E.K. Vanhoutte (MUMC+, Maastricht, The Netherlands), R.J.C. Admiraal, I. Feenstra, H. Kremer, H.P.M. Kunst, R.J.E. Pennings, H.G. Yntema (Radboudumc, Nijmegen, The Netherlands) A.J. van Essen, R.H. Free and J.S. Klein-Wassink (UMCG, Groningen, The Netherlands). The members of the DOOFNL Consortium group are listed in the ?Acknowledgements? section. The authors have no conflict of interest to declare.
Publisher Copyright:
© 2018, The Author(s).
PY - 2018/5/1
Y1 - 2018/5/1
N2 - 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.
AB - 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.
UR - https://www.scopus.com/pages/publications/85046826182
U2 - 10.1007/s00439-018-1880-5
DO - 10.1007/s00439-018-1880-5
M3 - Article
AN - SCOPUS:85046826182
SN - 0340-6717
VL - 137
SP - 389
EP - 400
JO - Human Genetics
JF - Human Genetics
IS - 5
ER -