Neurogenetics Laboratory, Howard Hughes Medical Institute, Department of Neurosciences, University of California, San Diego, La Jolla, CA 92093, USA.
Science. 2012 Oct 19;338(6105):394-7. doi: 10.1126/science.1224631. Epub 2012 Sep 6.
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.
自闭症谱系障碍是一种遗传性异质性综合征，其特征是在互惠社会互动方面存在障碍。现有的躯体治疗方法疗效有限。我们在自闭症、癫痫和智力残疾的近亲家庭中发现了 BCKDK（分支链酮酸脱氢酶激酶）基因的失活突变。编码的蛋白质负责磷酸化介导的分支链酮酸脱氢酶（BCKDH）E1α亚基的失活。纯合 BCKDK 突变患者显示 BCKDK 信使 RNA 和蛋白质减少，E1α磷酸化和血浆支链氨基酸减少。Bckdk 敲除小鼠显示出异常的大脑氨基酸谱和神经行为缺陷，这些缺陷可以通过饮食补充来改善。因此，由 BCKDK 突变引起的伴有智力残疾和癫痫的自闭症代表了一种潜在可治疗的综合征。
