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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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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The authors declare that they have no conflict of interest.
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