NUDT21-spanning CNVs lead to neuropsychiatric disease and altered MeCP2 abundance via alternative polyadenylation
- Baylor College of Medicine, United States
- Texas Children's Hospital, United States
- Cleveland Clinic Children's Hospital, United States
- University of Tennessee Health Science Center, United States
- Instituto Nacional de Saude da Mulher, da Criança e do Adolescente Fernandes Figueira, Brazil
Abstract
The brain is sensitive to the dose of MECP2 such that small fluctuations in protein quantity lead to neuropsychiatric disease. Despite the importance of MeCP2 levels to brain function, little is know about its regulation. Here, 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'UTR, resulting in an enrichment of inefficiently translated long-mRNA isoforms. Importantly, normalization of NUDT21 via siRNA-mediated knockdown in duplication-patient lymphoblasts restores MeCP2 to normal levels. In this study, 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.
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Human subjects: Following informed consent, approved by the InstitutionalReview Board for Human Subject Research at Baylor College of Medicine, we performed a comprehensive chart review of medical records and neuropsychological testing. A venous blood sample was provided by the probands in order to establish immortalized lymphoblastoid cell lines.
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© 2015, Zoghbi et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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NUDT21-spanning CNVs lead to neuropsychiatric disease and altered MeCP2 abundance via alternative polyadenylation
eLife 4:e10782.
https://doi.org/10.7554/eLife.10782
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