Journal
SCIENCE
Volume 338, Issue 6105, Pages 394-397Publisher
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/science.1224631
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Funding
- NIH [P01HD070494, R01NS048453, P30NS047101, RC2MH089956, K08MH087639, T32MH018268]
- Broad Institute [U54HG003067]
- Center for Inherited Disease Research for genotyping
- Simons Foundation Autism Research Initiative
- Veterans Administration Merit Award
- German Research Foundation
- American Academy of Child and Adolescent Psychiatry Pilot Research Award/Elaine Schlosser Lewis Fund
- American Psychiatric Association/Lilly Research Fellowship
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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 E1 alpha subunit of branched-chain ketoacid dehydrogenase (BCKDH). Patients with homozygous BCKDK mutations display reductions in BCKDK messenger RNA and protein, E1 alpha 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.
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