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Despite the importance of MeCP2 levels to brain function, little is known about its regulation. In this study, we report eleven individuals with neuropsychiatric disease and copy-number variations spanning NUDT21, which encodes a subunit of pre-mRNA cleavage factor Im. Investigations of MECP2 mRNA and protein abundance in patient-derived lymphoblastoid cells from one NUDT21 deletion and three duplication cases show that NUDT21 regulates MeCP2 protein quantity. Elevated NUDT21 increases usage of the distal polyadenylation site in the MECP2 3\u2032 UTR, resulting in an enrichment of inefficiently translated long mRNA isoforms. Furthermore, normalization of NUDT21 via siRNA-mediated knockdown in duplication patient lymphoblasts restores MeCP2 to normal levels. Ultimately, we identify NUDT21 as a novel candidate for intellectual disability and neuropsychiatric disease, and elucidate a mechanism of pathogenesis by MeCP2 dysregulation via altered alternative polyadenylation.<\/jats:p>","DOI":"10.7554\/elife.10782","type":"journal-article","created":{"date-parts":[[2015,8,27]],"date-time":"2015-08-27T07:50:04Z","timestamp":1440661804000},"source":"Crossref","is-referenced-by-count":75,"title":["NUDT21-spanning CNVs lead to neuropsychiatric disease and altered MeCP2 abundance via alternative polyadenylation"],"prefix":"10.7554","volume":"4","author":[{"given":"Vincenzo A","family":"Gennarino","sequence":"first","affiliation":[{"name":"Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, United States"},{"name":"Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Callison E","family":"Alcott","sequence":"additional","affiliation":[{"name":"Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, United States"},{"name":"Program in Developmental Biology, Baylor College of Medicine, Houston, United States"},{"name":"Medical Scientist Training Program, Baylor College of Medicine, Houston, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chun-An","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, United States"},{"name":"Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arindam","family":"Chaudhury","sequence":"additional","affiliation":[{"name":"Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, United States"},{"name":"Dan L. 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