2. Academic Validation
  3. Mutation of SLC9A1, encoding the major Na⁺/H⁺ exchanger, causes ataxia-deafness Lichtenstein-Knorr syndrome

Mutation of SLC9A1, encoding the major Na⁺/H⁺ exchanger, causes ataxia-deafness Lichtenstein-Knorr syndrome

  • Hum Mol Genet. 2015 Jan 15;24(2):463-70. doi: 10.1093/hmg/ddu461.
Claire Guissart 1,  Xiuju Li 2,  Bruno Leheup 3,  Nathalie Drouot 4,  Bettina Montaut-Verient 5,  Emmanuel Raffo 6,  Philippe Jonveaux 7,  Anne-Françoise Roux 8,  Mireille Claustres 1,  Larry Fliegel 2,  Michel Koenig 9
Affiliations

Affiliations

  • 1 INSERM U827, Montpellier F-34000, France Université Montpellier I, Montpellier F-34000, France Laboratoire de Génétique Moléculaire, Centre Hospitalier Universitaire (CHU) Montpellier, Montpellier F-34000, France.
  • 2 Department of Biochemistry, Faculty of Medicine, University of Alberta, Edmonton, AB, Canada.
  • 3 Service de Médecine Infantile et Génétique Clinique, Centre de Référence Syndrome Malformatif et Anomalies du Développement, CHU de Nancy Pôle Enfants, 54511 Vandoeuvre cedex, France INSERM U954, Faculté de Médecine, Université de Lorraine, 54505 Vandoeuvre cedex, France.
  • 4 Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), INSERM U964/CNRS UMR7104/Université de Strasbourg, Illkirch, France.
  • 5 Service d'Oto-Rhino-Laryngologie et de Chirurgie Cervico-Faciale, CHU de Nancy, Vandoeuvre, France.
  • 6 INSERM U954, Faculté de Médecine, Université de Lorraine, 54505 Vandoeuvre cedex, France Service de Neuropédiatrie, CHU de Nancy Pôle Enfants, 54511 Vandoeuvre cedex, France and.
  • 7 INSERM U954, Faculté de Médecine, Université de Lorraine, 54505 Vandoeuvre cedex, France Laboratoire de Génétique Médicale, CHU Nancy, INSERM U954, Université de Lorraine, Vandoeuvre, France.
  • 8 INSERM U827, Montpellier F-34000, France Laboratoire de Génétique Moléculaire, Centre Hospitalier Universitaire (CHU) Montpellier, Montpellier F-34000, France.
  • 9 INSERM U827, Montpellier F-34000, France Université Montpellier I, Montpellier F-34000, France Laboratoire de Génétique Moléculaire, Centre Hospitalier Universitaire (CHU) Montpellier, Montpellier F-34000, France Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), INSERM U964/CNRS UMR7104/Université de Strasbourg, Illkirch, France [email protected].
PMID: 25205112 DOI: 10.1093/hmg/ddu461
Abstract

Lichtenstein-Knorr syndrome is an autosomal recessive condition that associates sensorineural hearing loss and cerebellar ataxia. Here, we report the first identification of a gene involved in Lichtenstein-Knorr syndrome. By using a combination of homozygosity mapping and whole-exome sequencing, we identified the homozygous p.Gly305Arg missense mutation in SLC9A1 that segregates with the disease in a large consanguineous family. Mutant glycine 305 is a highly conserved amino acid present in the eighth transmembrane segment of all metazoan orthologues of NHE1, the Na(+)/H(+) exchanger 1, encoded by SLC9A1. We demonstrate that the p.Gly305Arg mutation causes the near complete de-glycosylation, mis-targeting and loss of proton pumping activity of NHE1. The comparison of our family with the phenotypes of spontaneous and knockout Slc9a1 murine models demonstrates that the association between ataxia and hearing loss is caused by complete or near complete loss of function of NHE1 and altered regulation of pHi in the central nervous system.

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