title: Mutation of SLC9A1, encoding the major Na⁺/H⁺ exchanger, causes ataxia-deafness Lichtenstein-Knorr syndrome.
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.
authors.affiliation: 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.
authors.forename: Claire
authors.initials: C
authors.lastname: Guissart
authors.affiliation: Department of Biochemistry, Faculty of Medicine, University of Alberta, Edmonton, AB, Canada.
authors.forename: Xiuju
authors.initials: X
authors.lastname: Li
authors.affiliation: 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.
authors.forename: Bruno
authors.initials: B
authors.lastname: Leheup
authors.affiliation: Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), INSERM U964/CNRS UMR7104/Université de Strasbourg, Illkirch, France.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Drouot
authors.affiliation: Service d'Oto-Rhino-Laryngologie et de Chirurgie Cervico-Faciale, CHU de Nancy, Vandoeuvre, France.
authors.forename: Bettina
authors.initials: B
authors.lastname: Montaut-Verient
authors.affiliation: 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.
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Raffo
authors.affiliation: 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.
authors.forename: Philippe
authors.initials: P
authors.lastname: Jonveaux
authors.affiliation: INSERM U827, Montpellier F-34000, France Laboratoire de Génétique Moléculaire, Centre Hospitalier Universitaire (CHU) Montpellier, Montpellier F-34000, France.
authors.forename: Anne-Françoise
authors.initials: AF
authors.lastname: Roux
authors.affiliation: 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.
authors.forename: Mireille
authors.initials: M
authors.lastname: Claustres
authors.affiliation: Department of Biochemistry, Faculty of Medicine, University of Alberta, Edmonton, AB, Canada.
authors.forename: Larry
authors.initials: L
authors.lastname: Fliegel
authors.affiliation: 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 michel.koenig@inserm.fr.
authors.forename: Michel
authors.initials: M
authors.lastname: Koenig
mesh_terms: D000818:Animals; D027682:Cation Transport Proteins / Q000235:genetics* / Q000378:metabolism; D002524:Cerebellar Ataxia / Q000235:genetics* / Q000378:metabolism; D003638:Deafness / Q000235:genetics* / Q000378:metabolism; D019066:Facies; D005260:Female; D005357:Fibrous Dysplasia of Bone / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D007153:Immunologic Deficiency Syndromes / Q000235:genetics* / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D020125:Mutation, Missense; D009503:Neutropenia / Q000235:genetics* / Q000378:metabolism; D000074082:Sodium-Hydrogen Exchanger 1; D017923:Sodium-Hydrogen Exchangers / Q000235:genetics* / Q000378:metabolism
chemical_list: D027682:Cation Transport Proteins; C490998:SLC9A1 protein, human; C490997:Slc9a1 protein, mouse; D000074082:Sodium-Hydrogen Exchanger 1; D017923:Sodium-Hydrogen Exchangers