{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T02:48:45Z","timestamp":1787021325442,"version":"build-2736575974"},"reference-count":41,"publisher":"The Company of Biologists","issue":"11","license":[{"start":{"date-parts":[[2023,11,29]],"date-time":"2023-11-29T00:00:00Z","timestamp":1701216000000},"content-version":"vor","delay-in-days":14,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/100000065","name":"National Institute of Neurological Disorders and Stroke","doi-asserted-by":"crossref","award":["R01NS113141"],"award-info":[{"award-number":["R01NS113141"]}],"id":[{"id":"10.13039\/100000065","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000065","name":"National Institute of Neurological Disorders and Stroke","doi-asserted-by":"crossref","award":["R01NS121618"],"award-info":[{"award-number":["R01NS121618"]}],"id":[{"id":"10.13039\/100000065","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Carney Institute for Brain Science"},{"DOI":"10.13039\/100006418","name":"Brown University","doi-asserted-by":"crossref","id":[{"id":"10.13039\/100006418","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2023,11,15]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>Christianson syndrome (CS) is an X-linked disorder resulting from loss-of-function (LoF) mutations in SLC9A6 encoding the endosomal Na+\/H+ exchanger 6 (NHE6). CS presents with developmental delay, seizures, intellectual disability, nonverbal status, postnatal microcephaly, and ataxia. To define transcriptome signatures of NHE6 LoF, we conducted in-depth RNA-sequencing (RNA-seq) analysis on a haploid NHE6 null cell model. CRIPSR\/Cas9 genome editing introduced multiple LoF mutations into SLC9A6 in the near haploid human cell line Hap1. Isogenic, paired parental controls were also studied. NHE6 mutant cell lines were confirmed to have intra-endosomal over-acidification as was seen in other NHE6 null cells. RNA-seq analysis was performed by two widely used pipelines: HISAT2-StringTie-DEseq2 and STAR-HTseq-DEseq2. We identified 1056 differentially expressed genes in mutant NHE6 lines, including genes associated with neurodevelopment, synapse function, voltage-dependent calcium channels, and neuronal signaling. Weighted gene co-expression network analysis was then applied and identified a critical module enriched for genes governing lysosome function. By identifying significantly changed gene expression that is associated with lysosomal mechanisms in NHE6-null cells, our analyses suggest that loss of NHE6 function may converge on mechanisms implicated in lysosome-related neurologic disease. Further, this haploid cell model will serve as an important tool for translational science in CS.<\/jats:p>","DOI":"10.1242\/bio.059778","type":"journal-article","created":{"date-parts":[[2023,9,25]],"date-time":"2023-09-25T08:36:23Z","timestamp":1695630983000},"source":"Crossref","is-referenced-by-count":1,"title":["Targeting NHE6 gene expression identifies lysosome and neurodevelopmental mechanisms in a haploid\n                    <i>in vitro<\/i>\n                    cell model"],"prefix":"10.1242","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2606-6668","authenticated-orcid":false,"given":"Qing","family":"Wu","sequence":"first","affiliation":[{"name":"Carney Institute for Brain Science and Brown Institute for Translational Science, Brown University 1 Center for Translational Neuroscience , , Providence, RI 02912 , USA"},{"name":"Center for Computational Molecular Biology, Brown University 2 , Center for Computational Molecular Biology, Providence, RI 02912 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9565-1230","authenticated-orcid":false,"given":"Li","family":"Ma","sequence":"additional","affiliation":[{"name":"Carney Institute for Brain Science and Brown Institute for Translational Science, Brown University 1 Center for Translational Neuroscience , , Providence, RI 02912 , USA"},{"name":"Brown University 3 Department of Molecular Biology, Cell Biology and Biochemistry , , Providence, RI 02912 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9129-6809","authenticated-orcid":false,"given":"Lena","family":"Joesch-Cohen","sequence":"additional","affiliation":[{"name":"Carney Institute for Brain Science and Brown Institute for Translational Science, Brown University 1 Center for Translational Neuroscience , , Providence, RI 02912 , USA"},{"name":"Center for Computational Molecular Biology, Brown University 2 , Center for Computational Molecular Biology, Providence, RI 02912 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7990-033X","authenticated-orcid":false,"given":"Michael","family":"Schmidt","sequence":"additional","affiliation":[{"name":"Carney Institute for Brain Science and Brown Institute for Translational Science, Brown University 1 Center for Translational Neuroscience , , Providence, RI 02912 , USA"},{"name":"Brown University 3 Department of Molecular Biology, Cell Biology and Biochemistry , , Providence, RI 02912 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4068-7153","authenticated-orcid":false,"given":"Ece D. Gamsiz","family":"Uzun","sequence":"additional","affiliation":[{"name":"Carney Institute for Brain Science and Brown Institute for Translational Science, Brown University 1 Center for Translational Neuroscience , , Providence, RI 02912 , USA"},{"name":"Center for Computational Molecular Biology, Brown University 2 , Center for Computational Molecular Biology, Providence, RI 02912 , USA"},{"name":"Alpert Medical School of Brown University 4 Department of Pathology and Laboratory Medicine , , Providence, RI 02912 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3430-3520","authenticated-orcid":false,"given":"Eric M.","family":"Morrow","sequence":"additional","affiliation":[{"name":"Carney Institute for Brain Science and Brown Institute for Translational Science, Brown University 1 Center for Translational Neuroscience , , Providence, RI 02912 , USA"},{"name":"Center for Computational Molecular Biology, Brown University 2 , Center for Computational Molecular Biology, Providence, RI 02912 , USA"},{"name":"Brown University 3 Department of Molecular Biology, Cell Biology and Biochemistry , , Providence, RI 02912 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"237","published-online":{"date-parts":[[2023,11,29]]},"reference":[{"key":"2023112909445614900_BIO059778C1","doi-asserted-by":"publisher","first-page":"166","DOI":"10.1093\/bioinformatics\/btu638","article-title":"HTSeq--a Python framework to work with high-throughput sequencing data","volume":"31","author":"Anders","year":"2015","journal-title":"Bioinformatics"},{"key":"2023112909445614900_BIO059778C2","doi-asserted-by":"publisher","first-page":"102","DOI":"10.3390\/jpm13010102","article-title":"Additive potentiation of R334W-CFTR function by novel small molecules","volume":"13","author":"Bacalhau","year":"2023","journal-title":"J. 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