{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,21]],"date-time":"2026-10-21T22:57:57Z","timestamp":1792623477134,"version":"4.5.0"},"reference-count":91,"publisher":"Oxford University Press (OUP)","issue":"8","license":[{"start":{"date-parts":[[2025,1,29]],"date-time":"2025-01-29T00:00:00Z","timestamp":1738108800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["T32 HD007502"],"award-info":[{"award-number":["T32 HD007502"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01 NS118580"],"award-info":[{"award-number":["R01 NS118580"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01 GM147078"],"award-info":[{"award-number":["R01 GM147078"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Vanderbilt University Stanley Cohen"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2025,4,6]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Tuberous Sclerosis Complex (TSC) is a debilitating developmental disorder characterized by a variety of clinical manifestations. While benign tumors in the heart, lungs, kidney, and brain are all hallmarks of the disease, the most severe symptoms of TSC are often neurological, including seizures, autism, psychiatric disorders, and intellectual disabilities. TSC is caused by loss of function mutations in the TSC1 or TSC2 genes and consequent dysregulation of signaling via mechanistic Target of Rapamycin Complex 1 (mTORC1). While TSC neurological phenotypes are well-documented, it is not yet known how early in neural development TSC1\/2-mutant cells diverge from the typical developmental trajectory. Another outstanding question is the contribution of homozygous-mutant cells to disease phenotypes and whether phenotypes are also present in the heterozygous-mutant populations that comprise the vast majority of cells in patients. Using TSC patient-derived isogenic induced pluripotent stem cells (iPSCs) with defined genetic changes, we observed aberrant early neurodevelopment in vitro, including misexpression of key proteins associated with lineage commitment and premature electrical activity. These alterations in differentiation were coincident with hundreds of differentially methylated DNA regions, including loci associated with key genes in neurodevelopment. Collectively, these data suggest that mutation or loss of TSC2 affects gene regulation and expression at earlier timepoints than previously appreciated, with implications for whether and how prenatal treatment should be pursued.<\/jats:p>","DOI":"10.1093\/hmg\/ddae199","type":"journal-article","created":{"date-parts":[[2025,1,22]],"date-time":"2025-01-22T15:20:10Z","timestamp":1737559210000},"page":"684-698","source":"Crossref","is-referenced-by-count":5,"title":["Human TSC2 mutant cells exhibit aberrations in early neurodevelopment accompanied by changes in the DNA Methylome"],"prefix":"10.1093","volume":"34","author":[{"given":"Mary-Bronwen L","family":"Chalkley","sequence":"first","affiliation":[{"name":"Department of Cell & Developmental Biology, Vanderbilt University School of Medicine , 1161 21st Ave S, Nashville, Tennessee , 37232,","place":["United States of America"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lindsey N","family":"Guerin","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Vanderbilt University School of Medicine , 1161 21st Ave S, Nashville, Tennessee , 37232,","place":["United States of America"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tenhir","family":"Iyer","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Vanderbilt University Medical Center , 1211 Medical Center Dr, Nashville, Tennessee , 37232,","place":["United States of America"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Samantha","family":"Mallahan","sequence":"additional","affiliation":[{"name":"Department of Cell & Developmental Biology, Vanderbilt University School of Medicine , 1161 21st Ave S, Nashville, Tennessee , 37232,","place":["United States of America"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sydney","family":"Nelson","sequence":"additional","affiliation":[{"name":"Department of Cell & Developmental Biology, Vanderbilt University School of Medicine , 1161 21st Ave S, Nashville, Tennessee , 37232,","place":["United States of America"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7044-2953","authenticated-orcid":false,"given":"Mustafa","family":"Sahin","sequence":"additional","affiliation":[{"name":"Rosamund Stone Zander Translational Neuroscience Center, Department of Neurology, Harvard Medical School , 25 Shattuck Street, Boston, Massachusetts , 02115,","place":["United States of America"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emily","family":"Hodges","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Vanderbilt University School of Medicine , 1161 21st Ave S, Nashville, Tennessee , 37232,","place":["United States of America"]},{"name":"Vanderbilt Genetics Institute, Vanderbilt University School of Medicine , 1161 21st Ave S, Nashville, TN , 37232,","place":["USA"]},{"name":"Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center , 2220 Pierce Ave, Nashville, TN , 37232,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kevin C","family":"Ess","sequence":"additional","affiliation":[{"name":"Department of Cell & Developmental Biology, Vanderbilt University School of Medicine , 1161 21st Ave S, Nashville, Tennessee , 37232,","place":["United States of America"]},{"name":"Department of Pediatrics, Vanderbilt University Medical Center , 1211 Medical Center Dr, Nashville, Tennessee , 37232,","place":["United States of America"]},{"name":"Department of Pediatrics - Neurology, University of Colorado Anschutz Medical Campus , 13123 E. 16th Ave., Aurora, Colorado , 80045,","place":["United States of America"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0439-0141","authenticated-orcid":false,"given":"Rebecca A","family":"Ihrie","sequence":"additional","affiliation":[{"name":"Department of Cell & Developmental Biology, Vanderbilt University School of Medicine , 1161 21st Ave S, Nashville, Tennessee , 37232,","place":["United States of America"]},{"name":"Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center , 2220 Pierce Ave, Nashville, TN , 37232,","place":["USA"]},{"name":"Department of Pediatrics - Neurology, University of Colorado Anschutz Medical Campus , 13123 E. 16th Ave., Aurora, Colorado , 80045,","place":["United States of America"]},{"name":"Department of Neurological Surgery, Vanderbilt University Medical Center , 1211 Medical Center Dr, Nashville, Tennessee , 37232,","place":["United States of America"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2025,1,29]]},"reference":[{"key":"2025040712181681300_ref1","doi-asserted-by":"crossref","first-page":"1345","DOI":"10.1056\/NEJMra055323","article-title":"The tuberous sclerosis complex","volume":"355","author":"Crino","year":"2006","journal-title":"N Engl J Med"},{"key":"2025040712181681300_ref2","doi-asserted-by":"crossref","first-page":"189","DOI":"10.1097\/WCO.0b013e32832c4ff5","article-title":"Tuberous sclerosis complex: a brave new world?","volume":"23","author":"Ess","year":"2010","journal-title":"Curr Opin Neurol"},{"key":"2025040712181681300_ref3","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1002\/epi4.12286","article-title":"Epilepsy in tuberous sclerosis complex: findings from the TOSCA study","volume":"4","author":"Nabbout","year":"2019","journal-title":"Epilepsia 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