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

Guissart, Claire; Li, Xiuju; Leheup, Bruno; Drouot, Nathalie; Montaut-Verient, Bettina; Raffo, Emmanuel; Jonveaux, Philippe; Roux, Anne‐Françoise; Claustres, Mireille; Fliegel, Larry; Kœnig, M.

doi:10.1093/hmg/ddu461

Cited by 44 publications

(42 citation statements)

References 17 publications

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“…AP1 cells were transiently transfected with wild type HA-tagged NHE1 cDNA [7]. Proteins present at the cell surface were labeled with sulfo-NHS-SS-biotin as described earlier [18] and immobilized streptavidin resin was used to remove cell surface labeled protein.…”

Section: Characterization Of Glycosylationmentioning

confidence: 99%

“…NHE1 also plays a clear role in mammalian development. Mice with a NHE1 deletion have decreased postnatal growth and increased mortality, ataxia and epileptic seizures [6] and we have recently demonstrated that homozygous expression of a defective NHE1 gene in humans results in disease, with a phenotype including hearing loss and cerebellar ataxia [7].…”

Section: Introductionmentioning

confidence: 99%

“…The plasmid pYN4+ has been described earlier [26] and contains the human NHE1 protein with a C-terminal HA (hemagglutinin) tag. We have earlier shown the cysteineless NHE1 (cNHE1) is fully functional [7].…”

Section: Introductionmentioning

confidence: 99%

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Topological analysis of the Na+/H+ exchanger

Liu

Basu

et al. 2015

Biochimica et Biophysica Acta (BBA) - Biomembranes

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The mammalian Na+/H+ exchanger isoform 1 (NHE1) is a ubiquitously expressed integral membrane protein present in mammalian cells. It is made up of a hydrophobic 500 amino acid membrane domain that transports and removes protons from within cells, and a regulatory intracellular cytosolic domain made of approximately 315 amino acids. Determining the structure of NHE1 is critical for both an understanding of the Na+/H+ exchange mechanism of transport, and in the design of new improved inhibitors for use in treatment of several diseases in which it is involved. Differing models of the NHE1 protein have been proposed. The first model suggested by two groups proposes that amino acids 1-500 form a 12 transmembrane segment spanning region in which amino acids 1-127 form two transmembrane segments, and amino acids 315-411 form a single transmembrane segment with membrane associated segments. A second model based on the structure of the Escherichia coli Na+/H+ exchanger protein proposes an overall similar topology, but suggests amino acids 1-127 are removed as a signal sequence and are not present in the mature protein. It also suggests a different topology of amino acids 315-411 to form three transmembrane segments. We used cysteine scanning accessibility and examination of glycosylation of the mature protein to characterize the NHE1 protein. Our results demonstrate that the model of NHE1 is correct which suggests that amino acids 1-127 form two transmembrane segments that remain connected to the mature protein, and the segment between amino acids 315-411 is one transmembrane segment.

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Section: Characterization Of Glycosylationmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Topological analysis of the Na+/H+ exchanger

Liu

Basu

et al. 2015

Biochimica et Biophysica Acta (BBA) - Biomembranes

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“…Human NHE1 mutations had not been identified until recently, when a non-synonymous Gly305Arg substitution was shown to cause Lichtenstein-Knorr syndrome, a rare, autosomal recessive disorder characterized by ataxia and neurosensory deafness, with onset of symptoms typically by 1–2 years of age [157]. The mutation removes a critical NHE1 glycosylation site, resulting in loss of NHE1 targeting to the plasma membrane and a consequent absence of NHE1 Na + –H + exchange activity.…”

Section: Nhe1 Function At the Systemic Levelmentioning

confidence: 99%

Na+–H+ exchanger-1 (NHE1) regulation in kidney proximal tubule

Parker

Myers

Schelling

2015

Cell. Mol. Life Sci.

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The ubiquitously expressed plasma membrane Na+–H+ exchanger NHE1 is a 12 transmembrane-spanning protein that directs important cell functions such as homeostatic intracellular volume and pH control. The 315 amino acid cytosolic tail of NHE1 binds plasma membrane phospholipids and multiple proteins that regulate additional, ion-translocation independent functions. This review focuses on NHE1 structure/function relationships, as well as the role of NHE1 in kidney proximal tubule functions, including pH regulation, vectorial Na+ transport, cell volume control and cell survival. The implications of these functions are particularly critical in the setting of progressive, albuminuric kidney diseases, where the accumulation of reabsorbed fatty acids leads to disruption of NHE1-membrane phospholipid interactions and tubular atrophy, which is a poor prognostic factor for progression to end stage renal disease. This review amplifies the vital role of the proximal tubule NHE1 Na+–H+ exchanger as a kidney cell survival factor.

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“…Mutations were found in WWOX in two families with childhood-onset HCA, generalised tonic-clonic epilepsy and mental retardation (SCAR12); while the knock-out mice present spontaneous and audiogenic seizures as well as balance disturbances [20]. In a family with ataxia and sensorineural hearing loss, a homozygous mutation in SLC9A1 was identified; in the spontaneous swe mutant mice, degeneration of deep cerebellar, vestibular and cochlear nuclei is reported [21]. In GRID2, loss-of-function mutations have been described in early-onset ataxia phenotypes with various accompanying symptoms, concordantly with hotfoot mice [22][23][24].…”

Section: A Bumper Harvest Of Novel Genesmentioning

confidence: 99%

Genetic landscape remodelling in spinocerebellar ataxias: the influence of next-generation sequencing

2015

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Hereditary cerebellar ataxias (HCAs) are clinically and genetically heterogeneous neurodegenerative disorders, characterised by a cerebellar syndrome and other neurological or non-neurological signs. So far, more than 20 genes have been described in autosomal dominant HCA; in autosomal recessive HCA, even more genes are involved, in often more complex phenotypes. Because of that complexity, the genetic diagnosis of these diseases is often based on the next-generation sequencing techniques. In this review paper, we discuss the major contributions that they have made to the genetic landscape of HCAs. Numerous novel genes have been identified; still more have recently been implicated in HCAs in addition to being responsible for other diseases. The phenotypic spectrum associated with a single gene constantly gains in complexity. Novel types of mutations or transmissions in known genes are regularly being identified. All these factors make genotype-phenotype correlations particularly difficult. Some but not all of this variability can be explained by different pathophysiological consequences (loss of function, gain of function, variable levels of haploinsufficiency). This also raises the question of modifier genes. Finally, we highlight some functional pathways that increasingly appear important in HCAs.

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

Cited by 44 publications

References 17 publications

Topological analysis of the Na+/H+ exchanger

Topological analysis of the Na+/H+ exchanger

Na+–H+ exchanger-1 (NHE1) regulation in kidney proximal tubule

Genetic landscape remodelling in spinocerebellar ataxias: the influence of next-generation sequencing

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