A novel SLC9A1 mutation causes cerebellar ataxia

Article metrics


The mammalian Na+/H+ exchanger isoform one (NHE1), encoded by Solute Carrier Family 9, member 1 (SLC9A1), consists of 12 membrane domains and a cytosolic C-terminal domain. NHE1 plays an important role in maintaining intracellular pH homeostasis by exchanging one intracellular proton for one extracellular sodium ion. Mice with a homozygous null mutation in Slc9a1 (Nhe1) exhibited ataxia, recurrent seizures, and selective neuronal cell death. In humans, three unrelated patients have been reported: a patient with a homozygous missense mutation in SLC9A1, c.913G>A (p.Gly305Arg), which caused Lichtenstein–Knorr syndrome characterized by cerebellar ataxia and sensorineural hearing loss, a patient with compound heterozygous mutations, c.1351A>C (p.Ile451Leu) and c.1585C>T (p.His529Tyr), which caused a neuromuscular disorder, and a patient with de novo mutation, c.796A>C (p.Asn266His) which associated multiple anomalies. In this study, using whole exome sequencing, we identified a novel homozygous SLC9A1 truncating mutation, c.862del (p.Ile288Serfs*9), in two affected siblings. The patients showed cerebellar ataxia but neither of them showed sensorineural hearing loss nor a neuromuscular phenotype. The main clinical feature was similar to Lichtenstein–Knorr syndrome but deafness may not be an essential phenotypic feature of SLC9A1 mutation. Our report expands the knowledge of clinical features of SLC9A1 mutations.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Fig. 1
Fig. 2
Fig. 3


  1. 1.

    Lee BL, Sykes BD, Fliegel L. Structural and functional insights into the cardiac Na(+)/H(+) exchanger. J Mol Cell Cardiol. 2013;61:60–7.

  2. 2.

    Fliegel L. Regulation of the Na(+)/H(+) exchanger in the healthy and diseased myocardium. Expert Opin Ther Targets. 2009;13:55–68.

  3. 3.

    Amith SR, Fliegel L. Regulation of the Na+/H+ Exchanger (NHE1) in Breast Cancer Metastasis. Cancer Res. 2013;73:1259–64.

  4. 4.

    Parks SK, Chiche J, Pouyssegur J. Disrupting proton dynamics and energy metabolism for cancer therapy. Nat Rev Cancer. 2013;13:611–23.

  5. 5.

    Cox GA, Lutz CM, Yang CL, Biemesderfer D, Bronson RT, Fu A, et al. Sodium/hydrogen exchanger gene defect in slow-wave epilepsy mutant mice. Cell . 1997;91:139–48.

  6. 6.

    Guissart C, Li X, Leheup B, Drouot N, Montaut-Verient B, Raffo E, et al. Mutation of SLC9A1, encoding the major Na(+)/H(+) exchanger, causes ataxia-deafness Lichtenstein-Knorr syndrome. Hum Mol Genet. 2015;24:463–70.

  7. 7.

    Miyatake S, Okamoto N, Stark Z, Nabetani M, Tsurusaki Y, Nakashima M, et al. ANKRD11 variants cause variable clinical features associated with KBG syndrome and Coffin-Siris-like syndrome. J Hum Genet. 2017;62:741–6.

  8. 8.

    Landau M, Herz K, Padan E, Ben-Tal N. Model structure of the Na+/H+ exchanger 1 (NHE1): functional and clinical implications. J Biol Chem. 2007;282:37854–63.

  9. 9.

    Koster S, Pavkov-Keller T, Kuhlbrandt W, Yildiz O. Structure of human Na+/H+ exchanger NHE1 regulatory region in complex with calmodulin and Ca2+. J Biol Chem. 2011;286:40954–61.

  10. 10.

    Farwell Hagman KD, Shinde DN, Mroske C, Smith E, Radtke K, Shahmirzadi L, et al. Candidate-gene criteria for clinical reporting: diagnostic exome sequencing identifies altered candidate genes among 8% of patients with undiagnosed diseases. Genet Med. 2017;19:224–35.

  11. 11.

    Zhu X, Petrovski S, Xie P, Ruzzo EK, Lu YF, McSweeney KM, et al. Whole-exome sequencing in undiagnosed genetic diseases: interpreting 119 trios. Genet Med. 2015;17:774–81.

  12. 12.

    Slepkov ER, Rainey JK, Li X, Liu Y, Cheng FJ, Lindhout DA, et al. Structural and functional characterization of transmembrane segment IV of the NHE1 isoform of the Na+/H+ exchanger. J Biol Chem. 2005;280:17863–72.

  13. 13.

    Alves C, Ma Y, Li X, Fliegel L. Characterization of human mutations in phosphorylatable amino acids of the cytosolic regulatory tail of SLC9A1. Biochem Cell Biol. 2014;92:524–9.

  14. 14.

    Lykke-Andersen S, Jensen TH. Nonsense-mediated mRNA decay: an intricate machinery that shapes transcriptomes. Nat Rev Mol Cell Biol. 2015;16:665–77.

  15. 15.

    Li X, Augustine A, Chen S, Fliegel L. Stop codon polymorphisms in the human SLC9A1 gene disrupt or compromise Na+/H+ exchanger function. PLoS ONE. 2016;11:e0162902.

  16. 16.

    Kirin M, McQuillan R, Franklin CS, Campbell H, McKeigue PM, Wilson JF. Genomic runs of homozygosity record population history and consanguinity. PLoS ONE. 2010;5:e13996.

  17. 17.

    McQuillan R, Leutenegger AL, Abdel-Rahman R, Franklin CS, Pericic M, Barac-Lauc L, et al. Runs of homozygosity in European populations. Am J Hum Genet. 2008;83:359–72.

Download references


We thank the individuals and their families for their participation in this study. We also thank Nobuko Watanabe and Mai Sato for technical assistance. We also thank Edanz Group (www.edanzediting.com/ac) for editing a draft of this manuscript. This work was supported by grants from Research on Measures for Intractable Diseases; Comprehensive Research on Disability Health and Welfare; the Strategic Research Program for Brain Science (SRPBS); the Practical Research Project for Rare/Intractable Diseases; the Initiative on Rare and Undiagnosed Diseases from the Japan Agency for Medical Research and Development; a Grant-in-Aid for Scientific Research on Innovative Areas (Transcription Cycle) from the Ministry of Education, Culture, Sports, Science and Technology of Japan; Grants-in-Aid for Scientific Research (A and B); Grant-in-Aid for Young Scientists (B); Challenging Exploratory Research from the Japan Society for the Promotion of Science; the fund for Creation of Innovation Centers for Advanced Interdisciplinary Research Areas Program in the Project for Developing Innovation Systems from the Japan Science and Technology Agency; grants from the Ministry of Health, Labour and Welfare; and the Takeda Science Foundation.

Author information

Correspondence to Naomichi Matsumoto.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Electronic supplementary material

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Further reading