Alternative titles; symbols
HGNC Approved Gene Symbol: SLC9A1
SNOMEDCT: 1237413006;
Cytogenetic location: 1p36.11 Genomic coordinates (GRCh38): 1:27,098,809-27,155,125 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 1p36.11 | Lichtenstein-Knorr syndrome | 616291 | Autosomal recessive | 3 |
The SLC9A1 gene encodes an Na+/H+ antiporter that is a ubiquitous membrane-bound enzyme involved in pH regulation of vertebrate cells. It is specifically inhibited by the diuretic drug amiloride and activated by a variety of signals including growth factors, mitogens, neurotransmitters, tumor promoters, and others (Mattei et al., 1988).
Mattei et al. (1987) used reverse genetics to clone the SLC9A1 gene. The gene was first disrupted in mouse fibroblasts. The lost function was then restored by transfection with human genomic DNA. Southern analysis of secondary and tertiary mouse transfectants demonstrated that unique EcoRI fragments containing 50 to 60 kb of human DNA were specifically retained in transfectants expressing Na+/H+ exchange activity (Franchi et al., 1986). Clones containing these specific human sequences were isolated. One genomic fragment was identified as an exon-coding sequence from the sodium-hydrogen ion antiporter gene by demonstration that it could complement antiporter deficiency in mouse cells; that it recognized an mRNA in cells expressing antiport activity but not in deficient cells; and that it was amplified in variants overexpressing antiport activity.
Sardet et al. (1989) presented the complete sequence of a cDNA encoding SLC9A1. The deduced 894-amino acid protein has a calculated molecular mass of 99.4 kD. It has 10 predicted transmembrane segments with cytoplasmic N and C termini. Northern blot analysis of mouse and human cells detected a 5.6-kb transcript.
Cox et al. (1997) reported that mouse Nhe1 has an N-terminal proton-sensing transporter domain, followed by 12 transmembrane segments and a long C-terminal regulatory domain.
Denker et al. (2000) showed that the plasma membrane ion exchanger NHE1 (SLC9A1) acts as an anchor for actin filaments to control the integrity of the cortical cytoskeleton. This occurs through a previously unrecognized structural link between NHE1 and the actin-binding proteins ezrin (123900), radixin (179410), and moesin (309845), which are collectively referred to as ERM proteins. NHE1 and ERM proteins were found to associate directly and colocalize in lamellipodia. Fibroblasts expressing NHE1 with mutations that disrupted binding with ERM proteins but not ion translocation had impaired organization of focal adhesions and actin stress fibers and an irregular cell shape. Denker et al. (2000) proposed a structural role for NHE1 in regulating the cortical cytoskeleton that is independent of its function as an ion exchanger.
Dudley et al. (1990) pointed out that SLC9A1 is a plausible candidate gene for human essential hypertension (145500).
Lifton et al. (1991) excluded linkage between elevated sodium-lithium countertransport, which is elevated in patients with essential hypertension, and the APNH gene. In an analysis of 93 hypertensive sib pairs, they further demonstrated that APNH explained none of the variance in sodium-lithium countertransport. They directly tested for linkage of APNH to genes predisposing to hypertension by analysis of linkage in hypertensive sib pairs. Mean allele sharing at APNH was not greater than expected from random assortment in hypertensive sibs.
Hisamitsu et al. (2012) found that human NHE1 directly bound calcineurin A (CANA, or PPP3CA; 114105) in the CANA-CANB (PPP3CB; 114106) dimer and promoted serum-induced NFAT (see 600490) nuclear translocation and signaling in human fibroblasts. Mutation analysis revealed that the sequence PVITID, encompassing residues 715 to 720, constitutes the CANA-binding motif of NHE1. NHE1 and CANA colocalized in membrane lipid rafts, and calcineurin activity was strongly enhanced at increased pH. NHE1-induced NFAT signaling required Na+/H+ exchange, suggesting that NHE1 may promote calcineurin-NFAT signaling by increasing pH at localized membrane microdomains. Overexpression of NHE1 also induced nuclear translocation of NFAT in primary rat cardiomyocytes and induced hypertrophic signaling.
The genomic probe reported by Mattei et al. (1987) was used to map the APNH gene to 1p36.1-p35 by in situ hybridization (Mattei et al., 1988). Mattei et al. (1989) used in situ hybridization of the human cDNA probe to map the antiporter gene to the distal portion of mouse chromosome 4 and to the long arm of Chinese hamster chromosome 2, confirming the conserved homology between the distal part of human chromosome 1p, the mouse distal 4, and Chinese hamster distal 2q. By the analysis of fragment length variations in recombinant inbred strains, Morahan and Rakar (1993) likewise mapped the Nhe1 gene to mouse chromosome 4, between Lck and Akp2. Lifton et al. (1990) used genomic clones of the SLC9A1 gene to identify 2 polymorphisms. Using these RFLPs in 59 reference families, they found that the antiporter gene lies 3 cM proximal to the RH locus. Dudley et al. (1990) PCR-amplified a 376-bp fragment corresponding to the 5-prime end of SLC9A1 and detected a polymorphism within this fragment by denaturing gradient gel electrophoresis. By genetic linkage studies, they mapped SLC9A1 telomeric to D1S57 and close to RH (111700) and ALPL (171760).
In 3 sibs, born of consanguineous Turkish parents, with Lichtenstein-Knorr syndrome (LIKNS; 616291), Guissart et al. (2015) identified a homozygous missense mutation in the SLC9A1 gene (G305R; 107310.0001). The mutation, which was found by a combination of homozygosity mapping and whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Exome sequencing of the SLC9A1 gene in 172 additional patients with ataxia or deafness did not identify any further mutations.
In 2 Han Chinese brothers with Lichtenstein-Knorr syndrome presenting as spinocerebellar ataxia, Iwama et al. (2018) identified a homozygous frameshift mutation in the SLC9A1 gene (107310.0003). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. The variant was not found in the ExAC database or in in-house controls. Although the parents were reportedly unrelated, haplotype analysis indicated a founder effect. Analysis of patient cells showed decreased mutant mRNA levels, consistent with nonsense-mediated mRNA decay. The patients did not have deafness.
Associations Pending Confirmation
For discussion of a possible association between de novo heterozygous variation in the SLC9A1 gene and a neurodevelopmental disorder, see 107310.0002.
In their Supplementary Table 5, Zhu et al. (2015) noted that a de novo heterozygous missense variant in the SLC9A1 gene (N266H) had been identified in a patient with spastic diplegia, autism, seizures, intellectual disability, and behavioral problems suggestive of Worster-Drought syndrome (185480). Li and Fliegel (2015) found that AP-1 CHO cells transfected with the N266H mutation had an approximately one-third reduction in mutant SLC9A1 protein levels compared to cells expressing wildtype SLC9A1. Despite normal targeting of the mutant protein to the cell membrane, the N266H mutant protein showed no significant transport activity. The mutation was postulated to occur in the transmembrane domain and may lie along the ion transduction pore.
Cox et al. (1997) reported the spontaneous autosomal recessive slow-wave epilepsy (swe) mouse mutation. Affected mice showed ataxic gait, which was most prominent in hindlimbs, by postnatal days 11 to 14. Swe/swe mice exhibited brief periods of behavioral arrest and developed tonic-clonic seizures. Less than half of swe/swe animals survived to weaning, and postmortem appearance suggested a lethal convulsive episode. Histologic analysis revealed that swe/swe mutants exhibited selective neuronal death in cerebellum and brainstem, but they had no other structural abnormalities. The onset and severity of the phenotype was influenced by genetic background, and heterozygous +/swe mice of any background were indistinguishable from wildtype. Cox et al. (1997) identified the swe mutation as a 1639A-T transversion in the Nhe1 gene, resulting in a premature stop codon after residue 441 that removed the entire C-terminal regulatory domain. In contrast with wildtype primary skin fibroblasts, those cultured from swe/swe mice displayed no appreciable uptake of radiolabeled sodium in response to acute acid load.
In 3 sibs, born of consanguineous Turkish parents, with Lichtenstein-Knorr syndrome (LIKNS; 616291), Guissart et al. (2015) identified a homozygous c.913G-A transition in exon 3 of the SLC9A1 gene (chr1.27,436,169C-T, GRCh37), resulting in a gly305-to-arg (G305R) substitution at a highly conserved residue in the eighth transmembrane segment. The mutation, which was found by a combination of homozygosity mapping and whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Transfection of the mutation into Chinese hamster ovary cells showed that it caused reduced expression of the mutant protein (about 33% of control levels). The mutant protein was hypoglycosylated, did not localize properly to the cell surface, and had only about 2% residual activity compared to wildtype.
This variant is classified as a variant of unknown significance because its contribution to a neurodevelopmental disorder has not been confirmed.
In a 6-year-old girl (from trio 48) with microcephaly, developmental delay, and seizures, Zhu et al. (2015) identified a de novo heterozygous c.1391C-T transition (c.1391C-T, ENST00000263980.3) in the SLC9A1 gene, resulting in a ser464-to-phe (S464F) substitution. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, was not detected in 3,027 in-house controls or in the Exome Sequencing Project database. Additional features in the patient included gingival hypertrophy, microdontia, intracranial calcification of the basal ganglia, and white matter abnormalities. Functional studies of the variant were not performed.
In 2 Han Chinese brothers, aged 8 and 3 years, with Lichtenstein-Knorr syndrome presenting as spinocerebellar ataxia (LIKNS; 616291), Iwama et al. (2018) identified a homozygous 1-bp deletion (c.862delA, NM_003047.4) in the SLC9A1 gene, resulting in a frameshift and premature termination (Ile288SerfsTer9). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. The variant was not found in the ExAC database or in in-house controls. Although the parents were reportedly unrelated, haplotype analysis indicated a founder effect. Analysis of patient cells showed decreased mutant mRNA levels, consistent with nonsense-mediated mRNA decay and a loss of function. The mutation was classified as pathogenic according to ACMG guidelines. The patients did not have deafness.
Cox, G. A., Lutz, C. M., Yang, C.-L., Biemesderfer, D., Bronson, R. T., Fu, A., Aronson, P. S., Noebels, J. L., Frankel, W. N. Sodium/hydrogen exchanger gene defect in slow-wave epilepsy mutant mice. Cell 91: 139-148, 1997. Note: Erratum: Cell 91: 860 only, 1997. [PubMed: 9335342] [Full Text: https://doi.org/10.1016/s0092-8674(01)80016-7]
Denker, S. P., Huang, D. C., Orlowski, J., Furthmayr, H., Barber, D. L. Direct binding of the Na-H exchanger NHE1 to ERM proteins regulates the cortical cytoskeleton and cell shape independently of H(+) translocation. Molec. Cell 6: 1425-1436, 2000. [PubMed: 11163215] [Full Text: https://doi.org/10.1016/s1097-2765(00)00139-8]
Dudley, C. R. K., Giuffra, L. A., Tippett, P., Kidd, K. K., Reeders, S. T. The Na+/H+ antiporter: a 'melt' polymorphism allows regional mapping to the short arm of chromosome 1. Hum. Genet. 86: 79-83, 1990. [PubMed: 1979310] [Full Text: https://doi.org/10.1007/BF00205179]
Franchi, A., Perucca-Lostanlen, D., Pouyssegur, J. Functional expression of a human Na+/H+ antiporter gene transfected into antiporter-deficient mouse L cells. Proc. Nat. Acad. Sci. 83: 9388-9392, 1986. [PubMed: 3025840] [Full Text: https://doi.org/10.1073/pnas.83.24.9388]
Guissart, C., Li, X., Leheup, B., Drouot, N., Montaut-Verient, B., Raffo, E., Jonveaux, P., Roux, A.-F., Claustres, M., Fliegel, L., Koenig, M. Mutation of SLC9A1, encoding the major Na+/H+ exchanger, causes ataxia-deafness Lichtenstein-Knorr syndrome. Hum. Molec. Genet. 24: 463-470, 2015. [PubMed: 25205112] [Full Text: https://doi.org/10.1093/hmg/ddu461]
Hisamitsu, T., Nakamura, T. Y., Wakabayashi, S. Na+/H+ exchanger 1 directly binds to calcineurin A and activates downstream NFAT signaling, leading to cardiomyocyte hypertrophy. Molec. Cell. Biol. 32: 3265-3280, 2012. [PubMed: 22688515] [Full Text: https://doi.org/10.1128/MCB.00145-12]
Iwama, K., Osaka, H., Ikeda, T., Mitsuhashi, S., Miyatake, S., Takata, A., Miyake, N. Ito, S., Mizuguchi, T., Matsumoto, N. A novel SLC9A1 mutation causes cerebellar ataxia. J. Hum. Genet. 63: 1049-1054, 2018. [PubMed: 30018422] [Full Text: https://doi.org/10.1038/s10038-018-0488-x]
Li, X., Fliegel, L. A novel human mutation in the SLC9A1 gene results in abolition of Na(+)/H(+) exchanger activity. PLoS One 10: e0119453, 2015. Note: Electronic Article. [PubMed: 25760855] [Full Text: https://doi.org/10.1371/journal.pone.0119453]
Lifton, R. P., Hunt, S. C., Williams, R. R., Pouyssegur, J., Lalouel, J. M. Exclusion of the Na(+)-H+ antiporter as a candidate gene in human essential hypertension. Hypertension 17: 8-14, 1991. [PubMed: 1846121] [Full Text: https://doi.org/10.1161/01.hyp.17.1.8]
Lifton, R. P., Sardet, C., Pouyssegur, J., Lalouel, J.-M. Cloning of the human genomic amiloride-sensitive Na+/H+ antiporter gene, identification of genetic polymorphisms, and localization on the genetic map of chromosome 1p. Genomics 7: 131-135, 1990. [PubMed: 1970796] [Full Text: https://doi.org/10.1016/0888-7543(90)90530-8]
Mattei, M.-G., Galloni, M., Sardet, C., Franchi, A., Counillon, L., Passage, E., Pouyssegur, J. Localization of the antiporter gene (APNH) and chromosomal homology between human 1p, mouse 4 and Chinese hamster 2q. (Abstract) Cytogenet. Cell Genet. 51: 1041, 1989.
Mattei, M.-G., Sardet, C., Franchi, A., Pouyssegur, J. Chromosomal mapping of the amiloride-sensitive Na+/H+ antiporter gene. (Abstract) Cytogenet. Cell Genet. 46: 658-659, 1987.
Mattei, M.-G., Sardet, C., Franchi, A., Pouyssegur, J. The human amiloride-sensitive Na+/H+ antiporter: localization to chromosome 1 by in situ hybridization. Cytogenet. Cell Genet. 48: 6-8, 1988. [PubMed: 2846238] [Full Text: https://doi.org/10.1159/000132575]
Mendoza, S. A. The Na+/H+ antiport is a mediator of cell proliferation. Acta Paediat. Scand. 76: 545-547, 1987. [PubMed: 2442956] [Full Text: https://doi.org/10.1111/j.1651-2227.1987.tb10518.x]
Morahan, G., Rakar, S. Localization of the mouse Na+/H+ exchanger gene on distal chromosome 4. Genomics 15: 231-232, 1993. [PubMed: 8094369] [Full Text: https://doi.org/10.1006/geno.1993.1044]
Sardet, C., Franchi, A., Pouyssegur, J. Molecular cloning, primary structure, and expression of the human growth factor-activatable Na(+)/H(+) antiporter. Cell 56: 271-280, 1989. [PubMed: 2536298] [Full Text: https://doi.org/10.1016/0092-8674(89)90901-x]
Zhu, X., Petrovski, S., Xie, P., Ruzzo, E. K., Lu, Y.-F., McSweeney, M., Ben-Zeev, B., Nissenkorn, A., Anikster, Y., Oz-Levi, D., Dhindsa, R. S., Hitomi, Y., and 15 others. Whole-exome sequencing in undiagnosed genetic diseases: interpreting 119 trios. Genet. Med. 17: 774-781, 2015. [PubMed: 25590979] [Full Text: https://doi.org/10.1038/gim.2014.191]