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

  1. Huda Y Zoghbi  Is a corresponding author
  2. Vincenzo A Gennarino
  3. Callison E Alcott
  4. Chun-An Chen
  5. Arindam Chaudhury
  6. Madelyn A Gillentine
  7. Jill A Rosenfeld
  8. Sumit Parikh
  9. James W Wheless
  10. Elizabeth R Roeder
  11. Dafne DG Horovitz
  12. Erin K Roney
  13. Janice L Smith
  14. Sau W Cheung
  15. Wei Li
  16. Joel R Neilson
  17. Christian P Schaaf
  1. Baylor College of Medicine, United States
  2. Texas Children's Hospital, United States
  3. Cleveland Clinic Children's Hospital, United States
  4. University of Tennessee Health Science Center, United States
  5. 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.

Article and author information

Author details

  1. Huda Y Zoghbi

    Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, United States
    For correspondence
    hzoghbi@bcm.edu
    Competing interests
    Huda Y Zoghbi, Senior editor, eLife.
  2. Vincenzo A Gennarino

    Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, United States
    Competing interests
    No competing interests declared.
  3. Callison E Alcott

    Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, United States
    Competing interests
    No competing interests declared.
  4. Chun-An Chen

    Departments of Molecular and Human Genetics, Baylor College of Medicine, Houston, United States
    Competing interests
    No competing interests declared.
  5. Arindam Chaudhury

    Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, United States
    Competing interests
    No competing interests declared.
  6. Madelyn A Gillentine

    Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, United States
    Competing interests
    No competing interests declared.
  7. Jill A Rosenfeld

    Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, United States
    Competing interests
    No competing interests declared.
  8. Sumit Parikh

    Center for Child Neurology, Cleveland Clinic Children's Hospital, Cleveland, United States
    Competing interests
    No competing interests declared.
  9. James W Wheless

    Department of Pediatric Neurology, Neuroscience Institute and Tuberous Sclerosis Clinic, Le Bonheur Children's Hospital, University of Tennessee Health Science Center, Memphis, United States
    Competing interests
    No competing interests declared.
  10. Elizabeth R Roeder

    Department of Pediatrics, Baylor College of Medicine, San Antonio, United States
    Competing interests
    No competing interests declared.
  11. Dafne DG Horovitz

    Depto de Genetica Medica, Instituto Nacional de Saude da Mulher, da Criança e do Adolescente Fernandes Figueira, Rio de Janeiro, Brazil
    Competing interests
    No competing interests declared.
  12. Erin K Roney

    Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, United States
    Competing interests
    No competing interests declared.
  13. Janice L Smith

    Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, United States
    Competing interests
    No competing interests declared.
  14. Sau W Cheung

    Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, United States
    Competing interests
    No competing interests declared.
  15. Wei Li

    Division of Biostatistics, Dan L Duncan Cancer Center, Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, United States
    Competing interests
    No competing interests declared.
  16. Joel R Neilson

    Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, United States
    Competing interests
    No competing interests declared.
  17. Christian P Schaaf

    Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, United States
    Competing interests
    No competing interests declared.

Ethics

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.

Reviewing Editor

  1. Harry C Dietz, Johns Hopkins University School of Medicine, United States

Publication history

  1. Received: August 11, 2015
  2. Accepted: August 26, 2015
  3. Accepted Manuscript published: August 27, 2015 (version 1)
  4. Accepted Manuscript updated: August 28, 2015 (version 2)
  5. Version of Record published: September 29, 2015 (version 3)

Copyright

© 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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  1. Huda Y Zoghbi
  2. Vincenzo A Gennarino
  3. Callison E Alcott
  4. Chun-An Chen
  5. Arindam Chaudhury
  6. Madelyn A Gillentine
  7. Jill A Rosenfeld
  8. Sumit Parikh
  9. James W Wheless
  10. Elizabeth R Roeder
  11. Dafne DG Horovitz
  12. Erin K Roney
  13. Janice L Smith
  14. Sau W Cheung
  15. Wei Li
  16. Joel R Neilson
  17. Christian P Schaaf
(2015)
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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