{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,13]],"date-time":"2026-05-13T22:29:09Z","timestamp":1778711349672,"version":"3.51.4"},"reference-count":41,"publisher":"Wiley","issue":"12","license":[{"start":{"date-parts":[[2023,6,28]],"date-time":"2023-06-28T00:00:00Z","timestamp":1687910400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["CNS Neurosci Ther"],"published-print":{"date-parts":[[2023,12]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Background<\/jats:title><jats:p>Christianson syndrome (CS) is caused by mutations in <jats:italic>SLC9A6<\/jats:italic> and is characterized by global developmental delay, epilepsy, hyperkinesis, ataxia, microcephaly, and behavioral disorder. However, the molecular mechanism by which these <jats:italic>SLC9A6<\/jats:italic> mutations cause CS in humans is not entirely understood, and there is no objective method to determine the pathogenicity of single <jats:italic>SLC9A6<\/jats:italic> variants.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Trio\u2010based whole exome sequencing (WES) was carried out on two individuals with suspicion of CS. qRT\u2010PCR, western blot analysis, filipin staining, lysosomal enzymatic assays, and electron microscopy examination, using EBV\u2010LCLs established from the two patients, were performed.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Trio\u2010based WES identified a hemizygous <jats:italic>SLC9A6<\/jats:italic> c.1560dupT, p.T521Yfs*23 variant in proband 1 and a hemizygous <jats:italic>SLC9A6<\/jats:italic> c.608delA, p.H203Lfs*10 variant in proband 2. Both children exhibited typical phenotypes associated with CS. Expression analysis in EBV\u2010LCLs derived from the two patients showed a significant decrease in mRNA levels and no detectable normal NHE6 protein. EBV\u2010LCLs showed a statistically significant increase in unesterified cholesterol in patient 1, but only non\u2010significant increase in patient 2 when stained with filipin. Activities of lysosomal enzymes (\u03b2\u2010hexosaminidase A, \u03b2\u2010hexosaminidase A\u2009+\u2009B, \u03b2\u2010galactosidase, galactocerebrosidase, arylsulfatase A) of EBV\u2010LCLs did not significantly differ between the two patients and six controls. Importantly, by electron microscopy we detected an accumulation of lamellated membrane structures, deformed mitochondria, and lipid droplets in the patients' EBV\u2010LCLs.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>The <jats:italic>SLC9A6<\/jats:italic> p.T521Yfs*23 and p.H203Lfs*10 variants in our patients result in loss of NHE6. Alterations of mitochondria and lipid metabolism may play a role in the pathogenesis of CS. Moreover, the combination of filipin staining with electron microscopy examination of patient lymphoblastoid cells can serve as a useful complementary diagnostic method for CS.<\/jats:p><\/jats:sec>","DOI":"10.1111\/cns.14329","type":"journal-article","created":{"date-parts":[[2023,6,29]],"date-time":"2023-06-29T06:54:55Z","timestamp":1688021695000},"page":"4059-4069","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Functional analysis of two <i>SLC9A6<\/i> frameshift variants in lymphoblastoid cells from patients with Christianson syndrome"],"prefix":"10.1111","volume":"29","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1095-4786","authenticated-orcid":false,"given":"Hailan","family":"He","sequence":"first","affiliation":[{"name":"Department of Pediatrics, Xiangya Hospital Central South University  Changsha China"},{"name":"Hunan Intellectual and Developmental Disabilities Research Center  Changsha 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