{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T23:11:09Z","timestamp":1760137869947,"version":"build-2065373602"},"reference-count":57,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2022,2,26]],"date-time":"2022-02-26T00:00:00Z","timestamp":1645833600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Medicina"],"abstract":"<jats:p>Background and Objectives: The pathogenic variants of SLC9A6 are a known cause of a rare, X-linked neurological disorder called Christianson syndrome (CS). The main characteristics of CS are developmental delay, intellectual disability, and neurological findings. This study investigated the genetic basis and explored the molecular changes that led to CS in two male siblings presenting with intellectual disability, epilepsy, behavioural problems, gastrointestinal dysfunction, poor height, and weight gain. Materials and Methods: Next-generation sequencing of a tetrad was applied to identify the DNA changes and Sanger sequencing of proband\u2019s cDNA was used to evaluate the impact of a splice site variant on mRNA structure. Bioinformatical tools were used to investigate SLC9A6 protein structure changes. Results: Sequencing and bioinformatical analysis revealed a novel donor splice site variant (NC_000023.11(NM_001042537.1):c.899 + 1G &gt; A) that leads to a frameshift and a premature stop codon. Protein structure modelling showed that the truncated protein is unlikely to form any functionally relevant SLC9A6 dimers. Conclusions: Molecular and bioinformatical analysis revealed the impact of a novel donor splice site variant in the SLC9A6 gene that leads to truncated and functionally disrupted protein causing the phenotype of CS in the affected individuals.<\/jats:p>","DOI":"10.3390\/medicina58030351","type":"journal-article","created":{"date-parts":[[2022,2,27]],"date-time":"2022-02-27T20:47:17Z","timestamp":1645994837000},"page":"351","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Donor Splice Site Variant in SLC9A6 Causes Christianson Syndrome in a Lithuanian Family: A Case Report"],"prefix":"10.3390","volume":"58","author":[{"given":"Gunda","family":"Petraityt\u0117","sequence":"first","affiliation":[{"name":"Department of Human and Medical Genetics, Institute of Biomedical Sciences, Faculty of Medicine, Vilnius University, LT-08661 Vilnius, Lithuania"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Violeta","family":"Mik\u0161tien\u0117","sequence":"additional","affiliation":[{"name":"Biobank of the Lithuanian Population and Rare Disorders, Institute of Biomedical Sciences, Faculty of Medicine, Vilnius University, LT-03101 Vilnius, Lithuania"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3110-4059","authenticated-orcid":false,"given":"Evelina","family":"Siavrien\u0117","sequence":"additional","affiliation":[{"name":"Department of Human and Medical Genetics, Institute of Biomedical Sciences, Faculty of Medicine, Vilnius University, LT-08661 Vilnius, Lithuania"},{"name":"Biobank of the Lithuanian Population and Rare Disorders, Institute of Biomedical Sciences, Faculty of Medicine, Vilnius University, LT-03101 Vilnius, Lithuania"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Loreta","family":"Cimbalistien\u0117","sequence":"additional","affiliation":[{"name":"Department of Human and Medical Genetics, Institute of Biomedical Sciences, Faculty of Medicine, Vilnius University, LT-08661 Vilnius, Lithuania"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"\u017divil\u0117","family":"Mald\u017eien\u0117","sequence":"additional","affiliation":[{"name":"Department of Human and Medical Genetics, Institute of Biomedical Sciences, Faculty of Medicine, Vilnius University, LT-08661 Vilnius, Lithuania"},{"name":"Biobank of the Lithuanian Population and Rare Disorders, Institute of Biomedical Sciences, Faculty of Medicine, Vilnius University, LT-03101 Vilnius, Lithuania"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1317-6334","authenticated-orcid":false,"given":"Tautvydas","family":"Ran\u010delis","sequence":"additional","affiliation":[{"name":"Department of Human and Medical Genetics, Institute of Biomedical Sciences, Faculty of Medicine, Vilnius University, LT-08661 Vilnius, Lithuania"},{"name":"Biobank of the Lithuanian Population and Rare Disorders, Institute of Biomedical Sciences, Faculty of Medicine, Vilnius University, LT-03101 Vilnius, Lithuania"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Evelina Marija","family":"Vait\u0117nien\u0117","sequence":"additional","affiliation":[{"name":"Department of Human and Medical Genetics, Institute of Biomedical Sciences, Faculty of Medicine, Vilnius University, LT-08661 Vilnius, Lithuania"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5631-7005","authenticated-orcid":false,"given":"Laima","family":"Ambrozaityt\u0117","sequence":"additional","affiliation":[{"name":"Department of Human and Medical Genetics, Institute of Biomedical Sciences, Faculty of Medicine, Vilnius University, LT-08661 Vilnius, Lithuania"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0496-6107","authenticated-orcid":false,"given":"Justas","family":"Dapk\u016bnas","sequence":"additional","affiliation":[{"name":"Department of Bioinformatics, Institute of Biotechnology, Life Sciences Center, Vilnius University, LT-10257 Vilnius, Lithuania"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ram\u016bnas","family":"Dzindzalieta","sequence":"additional","affiliation":[{"name":"Biobank of the Lithuanian Population and Rare Disorders, Institute of Biomedical Sciences, Faculty of Medicine, Vilnius University, LT-03101 Vilnius, Lithuania"},{"name":"Department of Software Engineering, Institute of Computer Science, Faculty of Mathematics and Informatics, Vilnius University, LT-03225 Vilnius, Lithuania"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1365-3564","authenticated-orcid":false,"given":"Erinija","family":"Pranckevi\u010dien\u0117","sequence":"additional","affiliation":[{"name":"Department of Human and Medical Genetics, Institute of Biomedical Sciences, Faculty of Medicine, Vilnius University, LT-08661 Vilnius, Lithuania"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6433-7305","authenticated-orcid":false,"given":"Vaidutis","family":"Ku\u010dinskas","sequence":"additional","affiliation":[{"name":"Department of Human and Medical Genetics, Institute of Biomedical Sciences, Faculty of Medicine, Vilnius University, LT-08661 Vilnius, Lithuania"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Algirdas","family":"Utkus","sequence":"additional","affiliation":[{"name":"Department of Human and Medical Genetics, Institute of Biomedical Sciences, Faculty of Medicine, Vilnius University, LT-08661 Vilnius, Lithuania"},{"name":"Biobank of the Lithuanian Population and Rare Disorders, Institute of Biomedical Sciences, Faculty of Medicine, Vilnius University, LT-03101 Vilnius, Lithuania"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Egl\u0117","family":"Preik\u0161aitien\u0117","sequence":"additional","affiliation":[{"name":"Department of Human and Medical Genetics, Institute of Biomedical Sciences, Faculty of Medicine, Vilnius University, LT-08661 Vilnius, Lithuania"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2022,2,26]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"796283","DOI":"10.3389\/fneur.2021.796283","article-title":"Case Report: Novel SLC9A6 Splicing Variant in a Chinese Boy with Christianson Syndrome With Electrical Status Epilepticus During Sleep","volume":"12","author":"Liu","year":"2022","journal-title":"Front. Neurol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1003","DOI":"10.1016\/j.ajhg.2008.01.013","article-title":"SLC9A6 Mutations Cause X-Linked Mental Retardation, Microcephaly, Epilepsy, and Ataxia, a Phenotype Mimicking Angelman Syndrome","volume":"82","author":"Gilfillan","year":"2008","journal-title":"Am. J. Hum. Genet."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"581","DOI":"10.1002\/ana.24225","article-title":"Genetic and phenotypic diversity of NHE6 mutations in Christianson syndrome","volume":"76","author":"Pescosolido","year":"2014","journal-title":"Ann. Neurol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"2775","DOI":"10.1002\/ajmg.a.33093","article-title":"Natural History of Christianson Syndrome","volume":"152A","author":"Schroer","year":"2010","journal-title":"Am. J. Med. Genet. Part A"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"841","DOI":"10.1007\/s00439-016-1675-5","article-title":"The expanding phenotypic spectrum of female SLC9A6 mutation carriers: A case series and review of the literature","volume":"135","author":"Sinajon","year":"2016","journal-title":"Hum. Genet."},{"key":"ref_6","first-page":"98","article-title":"Complex Neurological Phenotype in Female Carriers of NHE6 Mutations","volume":"5","author":"Pescosolido","year":"2019","journal-title":"Mol. Neuropsychiatry"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1359","DOI":"10.1007\/s00439-019-02081-x","article-title":"The genetic landscape of the human solute carrier (SLC) transporter superfamily","volume":"138","author":"Schaller","year":"2019","journal-title":"Hum. Genet."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1007\/s00424-013-1408-8","article-title":"Traditional and emerging roles for the SLC9 Na+\/H+ exchangers","volume":"466","author":"Fuster","year":"2014","journal-title":"Pflugers Arch. Eur. J. Physiol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"236","DOI":"10.1016\/j.mam.2012.05.001","article-title":"SLC9\/NHE gene family, a plasma membrane and organellar family of Na+\/H+ exchangers","volume":"34","author":"Donowitz","year":"2013","journal-title":"Mol. Asp. Med."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"172","DOI":"10.3389\/fncel.2014.00172","article-title":"An inside job: How endosomal Na+ \/H+ exchangers link to autism and neurological disease","volume":"8","author":"Kondapalli","year":"2014","journal-title":"Front. Cell. Neurosci."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1702","DOI":"10.1002\/jcp.22501","article-title":"High Capacity Na+\/H+ Exchange Activity in Mineralizing Osteoblasts","volume":"226","author":"Liu","year":"2011","journal-title":"J. Cell Physiol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"17387","DOI":"10.1074\/jbc.M101319200","article-title":"Molecular Cloning and Characterization of a Novel (Na+,K +)\/H+ Exchanger Localized to the transGolgi Network","volume":"276","author":"Numata","year":"2001","journal-title":"J. Biol. Chem."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"e164","DOI":"10.1093\/nar\/gkq603","article-title":"ANNOVAR: Functional annotation of genetic variants from high-throughput sequencing data","volume":"38","author":"Wang","year":"2010","journal-title":"Nucleic Acids Res."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"405","DOI":"10.1038\/gim.2015.30","article-title":"Standards and guidelines for the interpretation of sequence variants: A joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology","volume":"17","author":"Richards","year":"2015","journal-title":"Genet. Med."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"361","DOI":"10.1038\/nmeth.2890","article-title":"Mutationtaster2: Mutation prediction for the deep-sequencing age","volume":"11","author":"Schwarz","year":"2014","journal-title":"Nat. Methods"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"e67","DOI":"10.1093\/nar\/gkp215","article-title":"Human Splicing Finder: An online bioinformatics tool to predict splicing signals","volume":"37","author":"Desmet","year":"2009","journal-title":"Nucleic Acids Res."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"759","DOI":"10.1038\/ejhg.2008.257","article-title":"Ab initio prediction of mutation-induced cryptic splice-site activation and exon skipping","volume":"17","author":"Divina","year":"2009","journal-title":"Eur. J. Hum. Genet."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"3784","DOI":"10.1093\/nar\/gkg563","article-title":"ExPASy: The proteomics server for in-depth protein knowledge and analysis","volume":"31","author":"Gasteiger","year":"2003","journal-title":"Nucleic Acids Res."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"222","DOI":"10.1093\/nar\/gkt1223","article-title":"Pfam: The protein families database","volume":"42","author":"Finn","year":"2014","journal-title":"Nucleic Acids Res."},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"The UniProt Consortium (2019). UniProt: A worldwide hub of protein knowledge. Nucleic Acids Res., 47, D506\u2013D515.","DOI":"10.1093\/nar\/gky1049"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"2237","DOI":"10.1016\/j.jmb.2017.12.007","article-title":"A Completely Reimplemented MPI Bioinformatics Toolkit with a New HHpred Server at its Core","volume":"430","author":"Zimmermann","year":"2018","journal-title":"J. Mol. Biol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"935","DOI":"10.1093\/bioinformatics\/btw756","article-title":"The PPI3D web server for searching, analyzing and modeling protein-protein interactions in the context of 3D structures","volume":"33","author":"Dapkunas","year":"2017","journal-title":"Bioinformatics"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1735","DOI":"10.1016\/j.str.2013.08.005","article-title":"High-resolution comparative modeling with RosettaCM","volume":"21","author":"Song","year":"2013","journal-title":"Structure"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1496","DOI":"10.1073\/pnas.1914677117","article-title":"Improved protein structure prediction using predicted interresidue orientations","volume":"117","author":"Yang","year":"2020","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1002\/prot.22540","article-title":"Structure prediction for CASP8 with all-atom refinement using Rosetta","volume":"77","author":"Raman","year":"2009","journal-title":"Proteins"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1131","DOI":"10.1002\/prot.25278","article-title":"VoroMQA: Assessment of protein structure quality using interatomic contact areas","volume":"85","author":"Venclovas","year":"2017","journal-title":"Proteins"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"857","DOI":"10.1093\/bioinformatics\/btu744","article-title":"DISOPRED3: Precise disordered region predictions with annotated protein-binding activity","volume":"31","author":"Jones","year":"2015","journal-title":"Bioinformatics"},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Kozlowski, L.P., and Bujnicki, J.M. (2012). MetaDisorder: A meta-server for the prediction of intrinsic disorder in proteins. BMC Bioinform., 13.","DOI":"10.1186\/1471-2105-13-111"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1016\/bs.adgen.2018.09.002","article-title":"Understanding Human DNA Variants Affecting Pre-MRNA Splicing in the NGS Era","volume":"103","author":"Masotti","year":"2019","journal-title":"Adv. Genet."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"150","DOI":"10.1002\/humu.20400","article-title":"Single Base-Pair Substitutions in Exon\u2013Intron Junctions of Human Genes: Nature, Distribution, and Consequences for mRNA Splicing","volume":"28","author":"Krawczak","year":"2007","journal-title":"Hum. Mutat."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"253","DOI":"10.1007\/s13353-018-0444-7","article-title":"Splicing mutations in human genetic disorders: Examples, detection, and confirmation","volume":"59","author":"Abramowicz","year":"2018","journal-title":"J. Appl. Genet."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"e1378","DOI":"10.1002\/mgg3.1378","article-title":"Identification of novel splice mutation in SMAD3 in two Cypriot families with nonsyndromic thoracic aortic aneurysm. Two case reports","volume":"8","author":"Keravnou","year":"2020","journal-title":"Mol. Genet. Genom. Med."},{"key":"ref_33","first-page":"44","article-title":"Evaluation of the effect of c.2946 + 1G > T mutation on splicing in the SCN1A gene","volume":"54","author":"Mahmoud","year":"2015","journal-title":"Comput. Biol. Chem."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"4311","DOI":"10.1007\/s11033-013-2518-2","article-title":"Identification of an intronic regulatory mutation at the buffalo \u03b1s1-casein gene that triggers the skipping of exon 6","volume":"40","author":"Balteanu","year":"2013","journal-title":"Mol. Biol. Rep."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"6","DOI":"10.1038\/s41439-019-0046-x","article-title":"A novel splicing mutation in SLC9A6 in a boy with Christianson syndrome","volume":"6","author":"Ieda","year":"2019","journal-title":"Hum. Genome Var."},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Tian, C., Yan, R., Wen, S., Li, X., Li, T., Cai, Z., Li, X., Du, H., and Chen, H. (2014). A splice mutation and mRNA decay of EXT2 provoke hereditary multiple exostoses. PLoS ONE., 9.","DOI":"10.1371\/journal.pone.0094848"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1851","DOI":"10.1182\/blood-2002-03-0853","article-title":"Outcome of donor splice site mutations accounting for congenital afibrinogenemia reflects order of intron removal in the fibrinogen alpha gene (FGA)","volume":"101","author":"Attanasio","year":"2003","journal-title":"Blood"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"238","DOI":"10.1159\/000508562","article-title":"Comparative Functional Analysis in vitro of 2 COL4A5 Splicing Mutations at the Same Site in 2 Unrelated Alport Syndrome Chinese Families","volume":"160","author":"Lv","year":"2020","journal-title":"Cytogenet. Genome Res."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"802","DOI":"10.1261\/rna.876308","article-title":"Splicing regulation: From a parts list of regulatory elements to an integrated splicing code","volume":"14","author":"Wang","year":"2008","journal-title":"RNA"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"6294","DOI":"10.1093\/nar\/gkaa358","article-title":"Structural disruption of exonic stem\u2013loops immediately upstream of the intron regulates mammalian splicing","volume":"48","author":"Saha","year":"2020","journal-title":"Nucleic Acids Res."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"451","DOI":"10.1086\/342099","article-title":"Order of intron removal influences multiple splice outcomes, including a two-exon skip, in a COL5A1 acceptor-site mutation that results in abnormal pro-\u03b11(V) N-propeptides and Ehlers-Danlos syndrome type I","volume":"71","author":"Takahara","year":"2002","journal-title":"Am. J. Hum. Genet."},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"ymoens, S., Malfait, F., Vlummens, P., Hermanns-L\u00ea, T., Syx, D., and De Paepe, A. (2011). A novel splice variant in the N-propeptide of COL5A1 causes an EDS phenotype with severe kyphoscoliosis and eye involvement. PLoS ONE., 6.","DOI":"10.1371\/journal.pone.0020121"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"456","DOI":"10.1111\/ahg.12400","article-title":"RT-PCR analysis of mRNA revealed the splice-altering effect of rare intronic variants in monogenic disorders","volume":"84","author":"Zhang","year":"2020","journal-title":"Ann. Hum. Genet."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"799","DOI":"10.1002\/ajmg.b.31221","article-title":"A loss-of-function mutation in the SLC9A6 gene causes X-linked mental retardation resembling Angelman syndrome","volume":"156","author":"Takahashi","year":"2011","journal-title":"Am. J. Med. Genet. Part B Neuropsychiatr. Genet."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"461","DOI":"10.1242\/jcs.181008","article-title":"Nonsense-mediated mRNA decay in humans at a glance","volume":"129","author":"Kurosaki","year":"2016","journal-title":"J. Cell Sci."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"3014","DOI":"10.1016\/j.yexcr.2009.07.012","article-title":"Dual degradation mechanisms ensure disposal of NHE6 mutant protein associated with neurological disease","volume":"315","author":"Roxrud","year":"2009","journal-title":"Exp. Cell Res."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"ENEURO.0046-192019","DOI":"10.1523\/ENEURO.0046-19.2019","article-title":"Functional assessment in vivo of the mouse homolog of the human ala-9-ser NHE6 variant","volume":"6","author":"Ouyang","year":"2019","journal-title":"eNeuro"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"1031","DOI":"10.1152\/ajpcell.00420.2001","article-title":"Human Na+\/H+ exchanger isoform 6 is found in recycling endosomes of cells, not in mitochondria","volume":"282","author":"Brett","year":"2002","journal-title":"Am. J. Physiol.-Cell Physiol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1042\/BJ20060388","article-title":"Mutational analysis of the intramembranous H10 loop of yeast Nhx1 reveals a critical role in ion homoeostasis and vesicle trafficking","volume":"398","author":"Mukherjee","year":"2006","journal-title":"Biochem. J."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"1293","DOI":"10.1091\/mbc.e09-09-0767","article-title":"The Na_\/H_ Exchanger NHE6 in the Endosomal Recycling System Is Involved in the Development of Apical Bile Canalicular Surface Domains in HepG2 Cells","volume":"21","author":"Ohgaki","year":"2010","journal-title":"Mol. Biol. Cell"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"2083","DOI":"10.1002\/cphy.c110020","article-title":"Na+\/H+ exchangers","volume":"1","author":"Orlowski","year":"2011","journal-title":"Compr. Physiol."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"49221","DOI":"10.1074\/jbc.M106267200","article-title":"NHE6 Protein Possesses a Signal Peptide Destined for Endoplasmic Reticulum Membrane and Localizes in Secretory Organelles of the Cell","volume":"276","author":"Miyazaki","year":"2001","journal-title":"J. Biol. Chem."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"187","DOI":"10.1016\/j.nbd.2018.10.002","article-title":"A potential gain-of-function variant of SLC9A6 leads to endosomal alkalinization and neuronal atrophy associated with Christianson Syndrome","volume":"121","author":"Ilie","year":"2019","journal-title":"Neurobiol. Dis."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1016\/j.neuron.2013.07.043","article-title":"Christianson syndrome protein NHE6 modulates TrkB endosomal signaling required for neuronal circuit development","volume":"80","author":"Ouyang","year":"2013","journal-title":"Neuron"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"14426","DOI":"10.1073\/pnas.1312982110","article-title":"AMPA receptor pHluorin-GluA2 reports NMDA receptor-induced intracellular acidification in hippocampal neurons","volume":"110","author":"Rathje","year":"2013","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"106867","DOI":"10.1016\/j.nlm.2018.05.004","article-title":"Pathobiology of Christianson syndrome: Linking disrupted endosomal-lysosomal function with intellectual disability and sensory impairments","volume":"165","author":"Gulinello","year":"2019","journal-title":"Neurobiol. Learn. Mem."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"5311","DOI":"10.1074\/jbc.M114.602219","article-title":"The Na+\/H+ exchanger NHE6 modulates endosomal pH to control processing of amyloid precursor protein in a cell culture model of Alzheimer disease","volume":"290","author":"Prasad","year":"2015","journal-title":"J. Biol. Chem."}],"container-title":["Medicina"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1648-9144\/58\/3\/351\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T22:28:09Z","timestamp":1760135289000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1648-9144\/58\/3\/351"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,2,26]]},"references-count":57,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2022,3]]}},"alternative-id":["medicina58030351"],"URL":"https:\/\/doi.org\/10.3390\/medicina58030351","relation":{},"ISSN":["1648-9144"],"issn-type":[{"type":"electronic","value":"1648-9144"}],"subject":[],"published":{"date-parts":[[2022,2,26]]}}}