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Two Novel Mutations in the BCKDK (Branched‐Chain Keto‐Acid Dehydrogenase Kinase) Gene Are Responsible for a Neurobehavioral Deficit in Two Pediatric Unrelated Patients
Author(s) -
GarcíaCazorla Angels,
Oyarzabal Alfonso,
Fort Joana,
Robles Concepción,
Castejón Esperanza,
RuizSala Pedro,
Bodoy Susanna,
Merinero Begoña,
LopezSala Anna,
Dopazo Joaquín,
Nunes Virginia,
Ugarte Magdalena,
Artuch Rafael,
Palacín Manuel,
RodríguezPombo Pilar,
Alcaide Patricia,
Navarrete Rosa,
Sanz Paloma,
FontLlitjós Mariona,
Vilaseca Ma Antonia,
Ormaizabal Aida,
Pristoupilova Anna,
Agulló Sergi Beltran
Publication year - 2014
Publication title -
human mutation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 162
eISSN - 1098-1004
pISSN - 1059-7794
DOI - 10.1002/humu.22513
Subject(s) - missense mutation , biology , genetics , mutation , gene , exome sequencing , phenotype , biochemistry , endocrinology , medicine
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.520 C > G /p. R 174 G and c.1166 T > C /p. L 389 P , were identified at the homozygous state in two unrelated children with persistently reduced body fluid levels of branched‐chain amino acids ( BCAA s), developmental delay, microcephaly, and neurobehavioral abnormalities. Functional analysis of the mutations confirmed the missense character of the c.1166 T > C change and showed a splicing defect r.[520c>g;521_543del]/p. R 174 G fs1*, for c.520 C > G due to the presence of a new donor splice site. Mutation p. L 389 P showed total loss of kinase activity. Moreover, patient‐derived fibroblasts showed undetectable (p. R 174 G fs1*) or barely detectable (p. L 389 P ) levels of BCKDK protein and its phosphorylated substrate (phospho‐ E 1α), 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. R 174 G fs1*. 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.