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 W Wheless,
Elizabeth R Roeder,
Dafne DG Horovitz,
Erin K Roney,
Janice L Smith,
Sau W Cheung,
Wei Li,
Joel R Neilson,
Christian P Schaaf,
Huda Y Zoghbi
Affiliations
Vincenzo A Gennarino
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, United States; Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, United States
Callison E Alcott
Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, United States; Program in Developmental Biology, Baylor College of Medicine, Houston, United States; Medical Scientist Training Program, Baylor College of Medicine, Houston, United States
Chun-An Chen
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, United States; Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, United States
Arindam Chaudhury
Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, United States; Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, United States
Madelyn A Gillentine
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, United States; Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, United States
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, United States
Sumit Parikh
Center for Child Neurology, Cleveland Clinic Children's Hospital, Cleveland, United States
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
Elizabeth R Roeder
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, United States; Department of Pediatrics, Baylor College of Medicine, Houston, United States
Dafne DG Horovitz
Depto de Genetica Medica, Instituto Nacional de Saude da Mulher, da Criança e do Adolescente Fernandes Figueira, Rio de Janeiro, Brazil
Erin K Roney
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, United States
Janice L Smith
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, United States
Sau W Cheung
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, United States
Wei Li
Division of Biostatistics, Dan L Duncan Cancer Center, Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, United States
Joel R Neilson
Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, United States; Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, United States
Christian P Schaaf
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, United States; Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, United States
Huda Y Zoghbi
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, United States; Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, United States; Program in Developmental Biology, Baylor College of Medicine, Houston, United States; Department of Pediatrics, Baylor College of Medicine, Houston, United States; Howard Hughes Medical Institute, Baylor College of Medicine, Houston, United States
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.
