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A novel SLC9A1 mutation causes cerebellar ataxia

Abstract

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.

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References

  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.

    Article  PubMed  CAS  Google Scholar 

  2. 2.

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

    Article  PubMed  CAS  Google Scholar 

  3. 3.

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

    Article  PubMed  CAS  Google Scholar 

  4. 4.

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

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  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.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  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.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

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Acknowledgements

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.

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Correspondence to Naomichi Matsumoto.

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Iwama, K., Osaka, H., Ikeda, T. et al. A novel SLC9A1 mutation causes cerebellar ataxia. J Hum Genet 63, 1049–1054 (2018). https://doi.org/10.1038/s10038-018-0488-x

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