Year: 2012
Type: article
Study design: Observational Study
Abstract: Autism spectrum disorders are a genetically heterogeneous constellation of syndromes characterized by impairments in reciprocal social interaction. Available somatic treatments have limited efficacy. We have identified inactivating mutations in the gene BCKDK (Branched Chain Ketoacid Dehydrogenase Kinase) in consanguineous families with autism, epilepsy, and intellectual disability. The encoded protein is responsible for phosphorylation-mediated inactivation of the E1α subunit of branched-chain ketoacid dehydrogenase (BCKDH). Patients with homozygous BCKDK mutations display reductions in BCKDK messenger RNA and protein, E1α phosphorylation, and plasma branched-chain amino acids. Bckdk knockout mice show abnormal brain amino acid profiles and neurobehavioral deficits that respond to dietary supplementation. Thus, autism presenting with intellectual disability and epilepsy caused by BCKDK mutations represents a potentially treatable syndrome.
Source: Science
Authors: Gaia Novarino, Paul El-Fishawy, Hulya Kayserili, Nagwa A. Meguid, Eric M. Scott, Jana Schroth, Jennifer L. Silhavy, Majdi Kara, Rehab O. Khalil, Tawfeg Ben-Omran, A. Gulhan Ercan-Sencicek, Adel F. Hashish, Stephan J. Sanders, Abha R. Gupta, Hebatalla S. Hashem, Dietrich Matern, Stacey Gabriel, Larry Sweetman, Yasmeen Rahimi, Robert A. Harris, Matthew W. State, Joseph G. Gleeson
Institutions: Howard Hughes Medical Institute, University of California San Diego, Yale University, Istanbul University-Cerrahpaşa, Istanbul University, National Research Centre, Hamad Medical Corporation, Mayo Clinic, Broad Institute, Massachusetts Institute of Technology, Richard L. Roudebush VA Medical Center, Indiana University School of Medicine, Indiana University – Purdue University Indianapolis
Language: English
Subfield: Cognitive Neuroscience
Field: Neuroscience
Domain: Life Sciences
Open Access status: green
Funders: Howard Hughes Medical Institute, Eli Lilly and Company, Pfizer, Yale University, Broad Institute, Halozyme, Deutsche Forschungsgemeinschaft, National Institutes of Health, University of California, San Diego, Pfizer Pharmaceuticals, National Institute of Mental Health, National Human Genome Research Institute, National Institute of Neurological Disorders and Stroke, Eunice Kennedy Shriver National Institute of Child Health and Human Development
Awards: Doublecortin in Neuronal Migration, G1609525565, Molecular Characterization of Joubert Syndrome, G2851032130, Genomic Profiling and Functional Mutation Analysis in Autism Spectrum Disorders, G4353801355, G5440146302, University of California San Diego Neuroscience Microscopy Imaging Core, G639426234, G770899802, G8215682207, G9000005430, G9000022338, G9000125788
OpenAlex ID: W2005809131