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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.

NUDT21 -spanning CNVs lead to neuropsychiatric disease and altered MeCP2 abundance via alternative polyadenylation