Two novel mutations in the BCKDK (branched-chain keto-acid dehydrogenase kinase) gene are responsible for a neurobehavioral deficit in two pediatric unrelated patients.

TitleTwo novel mutations in the BCKDK (branched-chain keto-acid dehydrogenase kinase) gene are responsible for a neurobehavioral deficit in two pediatric unrelated patients.
Publication TypeJournal Article
Year of Publication2014
AuthorsGarcía-Cazorla, A, Oyarzabal, A, Fort, J, Robles, C, Castejón, E, Ruiz-Sala, P, Bodoy, S, Merinero, B, Lopez-Sala, A, Dopazo, J, Nunes, V, Ugarte, M, Artuch, R, Palacín, M, Rodríguez-Pombo, P, Alcaide, P, Navarrete, R, Sanz, P, Font-Llitjós, M, Vilaseca, MAntonia, Ormaizabal, A, Pristoupilova, A, Agulló, SBeltran
JournalHum Mutat
Volume35
Issue4
Pagination470-7
Date Published2014 Apr
ISSN1098-1004
KeywordsAmino Acids, Branched-Chain; Developmental Disabilities; Fibroblasts; Humans; Male; Mutation, Missense; Nervous System Diseases; Pediatrics; Protein Kinases
Abstract

Inactivating mutations in the BCKDK gene, which codes for the kinase responsible for the negative regulation of the branched-chain α-keto acid dehydrogenase complex (BCKD), have recently been associated with a form of autism in three families. In this work, two novel exonic BCKDK mutations, c.520C>G/p.R174G and c.1166T>C/p.L389P, were identified at the homozygous state in two unrelated children with persistently reduced body fluid levels of branched-chain amino acids (BCAAs), developmental delay, microcephaly, and neurobehavioral abnormalities. Functional analysis of the mutations confirmed the missense character of the c.1166T>C change and showed a splicing defect r.[520c>g;521_543del]/p.R174Gfs1*, for c.520C>G due to the presence of a new donor splice site. Mutation p.L389P showed total loss of kinase activity. Moreover, patient-derived fibroblasts showed undetectable (p.R174Gfs1*) or barely detectable (p.L389P) levels of BCKDK protein and its phosphorylated substrate (phospho-E1α), resulting in increased BCKD activity and the very rapid BCAA catabolism manifested by the patients' clinical phenotype. Based on these results, a protein-rich diet plus oral BCAA supplementation was implemented in the patient homozygous for p.R174Gfs1*. This treatment normalized plasma BCAA levels and improved growth, developmental and behavioral variables. Our results demonstrate that BCKDK mutations can result in neurobehavioral deficits in humans and support the rationale for dietary intervention.

DOI10.1002/humu.22513
Alternate JournalHum Mutat
PubMed ID24449431