TY - JOUR TI - NUDT21-spanning CNVs lead to neuropsychiatric disease and altered MeCP2 abundance via alternative polyadenylation AU - Gennarino, Vincenzo A AU - Alcott, Callison E AU - Chen, Chun-An AU - Chaudhury, Arindam AU - Gillentine, Madelyn A AU - Rosenfeld, Jill A AU - Parikh, Sumit AU - Wheless, James W AU - Roeder, Elizabeth R AU - Horovitz, Dafne DG AU - Roney, Erin K AU - Smith, Janice L AU - Cheung, Sau W AU - Li, Wei AU - Neilson, Joel R AU - Schaaf, Christian P AU - Zoghbi, Huda Y A2 - Dietz, Harry C VL - 4 PY - 2015 DA - 2015/08/27 SP - e10782 C1 - eLife 2015;4:e10782 DO - 10.7554/eLife.10782 UR - https://doi.org/10.7554/eLife.10782 AB - 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 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′ 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. KW - alternative polyadenylation KW - neuropsychiatric disease KW - NUDT21 KW - MeCP2 KW - intellectual disability JF - eLife SN - 2050-084X PB - eLife Sciences Publications, Ltd ER -