Mutation of SLC9A1, encoding the major Naâº/H⺠exchanger, causes ataxia-deafness Lichtenstein-Knorr syndrome.
Hum Mol Genet
; 24(2): 463-70, 2015 Jan 15.
Article
en En
| MEDLINE
| ID: mdl-25205112
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.
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Ataxia Cerebelosa
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Intercambiadores de Sodio-Hidrógeno
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Mutación Missense
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Proteínas de Transporte de Catión
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Sordera
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Displasia Fibrosa Ósea
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Síndromes de Inmunodeficiencia
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Neutropenia
Tipo de estudio:
Etiology_studies
Límite:
Animals
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Female
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Humans
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Male
Idioma:
En
Revista:
Hum Mol Genet
Asunto de la revista:
BIOLOGIA MOLECULAR
/
GENETICA MEDICA
Año:
2015
Tipo del documento:
Article
País de afiliación:
Francia
Pais de publicación:
ENGLAND
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ESCOCIA
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GB
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GREAT BRITAIN
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INGLATERRA
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REINO UNIDO
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SCOTLAND
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UK
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UNITED KINGDOM