Mutations in BCKD-kinase Lead to a Potentially Treatable Form of Autism with Epilepsy

作者：Novarino Gaia^*; El Fishawy Paul; Kayserili Hulya; Meguid Nagwa A; Scott Eric M; Schroth Jana; Silhavy Jennifer L; Kara Majdi; Khalil Rehab O; Ben Omran Tawfeg; Ercan Sencicek A Gulhan; Hashish Adel F; Sanders Stephan J; Gupta Abha R; Hashem Hebatalla S; Matern Dietrich; Gabriel Stacey; Sweetman Larry; Rahimi Yasmeen; Harris Robert A; State Matthew W; Gleeson Joseph G

来源：Science, 2012, 338(6105): 394-397.

DOI：10.1126/science.1224631

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.

• 出版日期2012-10-19