Two Novel Mutations in theBCKDK(Branched-Chain Keto-Acid Dehydrogenase Kinase) Gene Are Responsible for a Neurobehavioral Deficit in Two Pediatric Unrelated Patients
| Autor: | Begoña Merinero, Concepción Robles, Joana Fort, Aida Ormaizabal, Mariona Font-Llitjós, Joaquín Dopazo, Alfonso Oyarzabal, Patricia Alcaide, Pedro Ruiz-Sala, Anna López-Sala, Anna Pristoupilova, Magdalena Ugarte, Rosa Navarrete, Susanna Bodoy, Ma Antonia Vilaseca, Esperanza Castejón, Virginia Nunes, Angels García-Cazorla, Rafael Artuch, Sergi Beltran Agulló, Manuel Palacín, Pilar Rodríguez-Pombo, P. Sanz |
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| Rok vydání: | 2014 |
| Předmět: |
Male
medicine.medical_specialty Microcephaly Developmental Disabilities Mutation Missense BCKDK Biology medicine.disease_cause Pediatrics Internal medicine Genetics medicine Humans Missense mutation Kinase activity Gene Genetics (clinical) Mutation Kinase Catabolism Fibroblasts medicine.disease Endocrinology Nervous System Diseases Protein Kinases Amino Acids Branched-Chain |
| Zdroj: | Human Mutation. 35:470-477 |
| ISSN: | 1059-7794 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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