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

Vincenzo A. Gennarino, Callison E. Alcott, Chun An Chen, Arindam Chaudhury, Madelyn A. Gillentine, Jill A. Rosenfeld, Sumit Parikh, James Wheless, Elizabeth R. Roeder, Dafne D.G. Horovitz, Erin K. Roney, Janice L. Smith, Sau W. Cheung, Wei Li, Joel R. Neilson, Christian P. Schaaf, Huda Y. Zoghbi

Research output: Contribution to journalArticle

24 Citations (Scopus)

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.

Original languageEnglish (US)
Article numbere10782
JournaleLife
Volume4
Issue numberAUGUST2015
DOIs
StatePublished - Aug 27 2015

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Polyadenylation
Brain
Methyl-CpG-Binding Protein 2
RNA Isoforms
RNA Precursors
3' Untranslated Regions
Intellectual Disability
Small Interfering RNA
Proteins
Messenger RNA

All Science Journal Classification (ASJC) codes

  • Neuroscience(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)

Cite this

Gennarino, V. A., Alcott, C. E., Chen, C. A., Chaudhury, A., Gillentine, M. A., Rosenfeld, J. A., ... Zoghbi, H. Y. (2015). NUDT21-spanning CNVs lead to neuropsychiatric disease and altered MeCP2 abundance via alternative polyadenylation. eLife, 4(AUGUST2015), [e10782]. https://doi.org/10.7554/eLife.10782

NUDT21-spanning CNVs lead to neuropsychiatric disease and altered MeCP2 abundance via alternative polyadenylation. / Gennarino, Vincenzo A.; Alcott, Callison E.; Chen, Chun An; Chaudhury, Arindam; Gillentine, Madelyn A.; Rosenfeld, Jill A.; Parikh, Sumit; Wheless, James; Roeder, Elizabeth R.; Horovitz, Dafne D.G.; Roney, Erin K.; Smith, Janice L.; Cheung, Sau W.; Li, Wei; Neilson, Joel R.; Schaaf, Christian P.; Zoghbi, Huda Y.

In: eLife, Vol. 4, No. AUGUST2015, e10782, 27.08.2015.

Research output: Contribution to journalArticle

Gennarino, VA, Alcott, CE, Chen, CA, Chaudhury, A, Gillentine, MA, Rosenfeld, JA, Parikh, S, Wheless, J, Roeder, ER, Horovitz, DDG, Roney, EK, Smith, JL, Cheung, SW, Li, W, Neilson, JR, Schaaf, CP & Zoghbi, HY 2015, 'NUDT21-spanning CNVs lead to neuropsychiatric disease and altered MeCP2 abundance via alternative polyadenylation', eLife, vol. 4, no. AUGUST2015, e10782. https://doi.org/10.7554/eLife.10782
Gennarino VA, Alcott CE, Chen CA, Chaudhury A, Gillentine MA, Rosenfeld JA et al. NUDT21-spanning CNVs lead to neuropsychiatric disease and altered MeCP2 abundance via alternative polyadenylation. eLife. 2015 Aug 27;4(AUGUST2015). e10782. https://doi.org/10.7554/eLife.10782
Gennarino, Vincenzo A. ; Alcott, Callison E. ; Chen, Chun An ; Chaudhury, Arindam ; Gillentine, Madelyn A. ; Rosenfeld, Jill A. ; Parikh, Sumit ; Wheless, James ; Roeder, Elizabeth R. ; Horovitz, Dafne D.G. ; Roney, Erin K. ; Smith, Janice L. ; Cheung, Sau W. ; Li, Wei ; Neilson, Joel R. ; Schaaf, Christian P. ; Zoghbi, Huda Y. / NUDT21-spanning CNVs lead to neuropsychiatric disease and altered MeCP2 abundance via alternative polyadenylation. In: eLife. 2015 ; Vol. 4, No. AUGUST2015.
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