De novo missense variants in PPP2R5D are associated with intellectual disability, macrocephaly, hypotonia, and autism
| Autor: | Jason Carmichael, Jeffrey W. Innis, Donald S. Petrey, Linshan Shang, Katrina Haude, Jane L. Schuette, Megan T. Cho, Lindsay B. Henderson, Wendy K. Chung, Kyle Retterer, Margaret Pearson, Chin-To Fong, Leandra Folk, Julie Lundberg, Shailesh Asaikar, Kristin G. Monaghan, Natasha Shur, Yvonne W. Wu, Natalie Hauser |
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| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Male Autism Spectrum Disorder Autism DNA Mutational Analysis Intellectual disabilities Missense mutation 2.1 Biological and endogenous factors Protein Phosphatase 2 Aetiology Child Genetics (clinical) Genetics Pediatric Single Nucleotide Hypotonia PPP2R5D Mental Health Protein phosphatase Child Preschool Whole-exome sequencing Muscle Hypotonia Female Cognitive Sciences medicine.symptom Adolescent Protein subunit Intellectual and Developmental Disabilities (IDD) 1.1 Normal biological development and functioning Phosphatase Mutation Missense Biology Polymorphism Single Nucleotide Article Chromatin remodeling 03 medical and health sciences Cellular and Molecular Neuroscience Underpinning research Intellectual Disability medicine Humans Genetic Predisposition to Disease Autistic Disorder Polymorphism Preschool Protein kinase B GSK3B Genetic Association Studies De novo mutations Neurology & Neurosurgery Neurosciences Infant Protein phosphatase 2 Megalencephaly Brain Disorders 030104 developmental biology Mutation Missense |
| Zdroj: | Neurogenetics, vol 17, iss 1 |
| Popis: | Protein phosphatase 2A (PP2A) is a heterotrimeric protein serine/threonine phosphatase and is involved in a broad range of cellular processes. PPP2R5D is a regulatory B subunit of PP2A and plays an important role in regulating key neuronal and developmental regulation processes such as PI3K/AKT and glycogen synthase kinase 3 beta (GSK3β)-mediated cell growth, chromatin remodeling, and gene transcriptional regulation. Using whole-exome sequencing (WES), we identified four de novo variants in PPP2R5D in a total of seven unrelated individuals with intellectual disability (ID) and other shared clinical characteristics, including autism spectrum disorder, macrocephaly, hypotonia, seizures, and dysmorphic features. Among the four variants, two have been previously reported and two are novel. All four amino acids are highly conserved among the PP2A subunit family, and all change a negatively charged acidic glutamic acid (E) to a positively charged basic lysine (K) and are predicted to disrupt the PP2A subunit binding and impair the dephosphorylation capacity. Our data provides further support for PPP2R5D as a genetic cause of ID. |
| Databáze: | OpenAIRE |
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