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 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.
Highlights
Methyl CpG-binding protein 2 (MeCP2) binds methylated cytosines (Lewis et al, 1992, Guo et al, 2014) and affects the expression of thousands of genes (Chahrour et al, 2008)
Gennarino, Alcott et al grew cells in the laboratory from patients with extra copies of the NUDT21 gene and found that reducing the production of its protein returned the levels of the MeCP2 protein back to normal. These findings show that alterations in the NUDT21 gene cause changes in the level of MeCP2 protein in cells and leads to neuropsychiatric diseases
MECP2 loss-of-function is the predominant cause of Rett syndrome, a postnatal neurological disorder that typically manifests around 18 months of age with developmental regression (Amir et al, 1999; Ravn et al, 2005; Pan et al, 2006)
Summary
Methyl CpG-binding protein 2 (MeCP2) binds methylated cytosines (Lewis et al, 1992, Guo et al, 2014) and affects the expression of thousands of genes (Chahrour et al, 2008). We found that the NUDT21-duplication patients translate MECP2 less efficiently than healthy controls, with a ∼50% reduction in total MECP2 mRNA in the polyribosome fraction and a dramatic enrichment of the long isoform in the non-polyribosome fraction (Figure 3B) These data support the hypothesis that NUDT21-duplication patients have decreased MeCP2 protein despite increased mRNA because NUDT21 promotes distal APA site usage and the elevated RNA pool consists largely of the inefficiently translated long MECP2 isoform (Figure 3C). The clinical presentation of the three individuals with increased NUDT21 copy number and decreased MeCP2 protein levels is not that of classic Rett syndrome, which is not surprising since individuals with Rett lack the protein in 50% of their cells, whereas the duplication of NUDT21 causes a partial decrease in all cells These individuals suffer from intellectual disability and autism spectrum disorder, and two of the three individuals manifested significant developmental regression, which is a rare clinical phenomenon and considered a hallmark of Rett syndrome. The better we understand gene networks, gene-protein, and protein– protein interactions, the better we will be positioned to identify the molecular bases of various neuropsychiatric disorders and design treatment strategies for the affected individuals
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