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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

Authors

  • Angels García-Cazorla,

    1. Department of Neurology, Hospital Sant Joan de Déu (HSJD), CIBER de Enfermedades Raras (CIBERER), Barcelona, Spain
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    • These authors contributed equally to this work.

  • Alfonso Oyarzabal,

    1. Centro de Diagnóstico de Enfermedades Moleculares (CEDEM), Centro de Biología Molecular “Severo Ochoa” CSIC-UAM, Departamento de Biología Molecular, Universidad Autónoma de Madrid, CIBER de Enfermedades Raras (CIBERER), IDIPAZ, Madrid, Spain
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    • These authors contributed equally to this work.

  • Joana Fort,

    1. Institute for Research in Biomedicine (IRB Barcelona), Department of Biochemistry and Molecular Biology, Faculty of Biology, University of Barcelona, CIBER de Enfermedades Raras (CIBERER), Barcelona, Spain
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    • These authors contributed equally to this work.

  • Concepción Robles,

    1. Paediatrics’ Department, San Cecilio Hospital, Granada, Spain
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  • Esperanza Castejón,

    1. Department of Gastroenterology, Hospital Sant Joan de Déu (HSJD), Barcelona, Spain
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  • Pedro Ruiz-Sala,

    1. Centro de Diagnóstico de Enfermedades Moleculares (CEDEM), Centro de Biología Molecular “Severo Ochoa” CSIC-UAM, Departamento de Biología Molecular, Universidad Autónoma de Madrid, CIBER de Enfermedades Raras (CIBERER), IDIPAZ, Madrid, Spain
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  • Susanna Bodoy,

    1. Institute for Research in Biomedicine (IRB Barcelona), Department of Biochemistry and Molecular Biology, Faculty of Biology, University of Barcelona, CIBER de Enfermedades Raras (CIBERER), Barcelona, Spain
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  • Begoña Merinero,

    1. Centro de Diagnóstico de Enfermedades Moleculares (CEDEM), Centro de Biología Molecular “Severo Ochoa” CSIC-UAM, Departamento de Biología Molecular, Universidad Autónoma de Madrid, CIBER de Enfermedades Raras (CIBERER), IDIPAZ, Madrid, Spain
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  • Anna Lopez-Sala,

    1. Department of Neurology, Hospital Sant Joan de Déu (HSJD), CIBER de Enfermedades Raras (CIBERER), Barcelona, Spain
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  • Joaquín Dopazo,

    1. Computational Genomics Department, Centro de Investigación Príncipe Felipe (CIPF), Valencia, Spain
    2. Functional Genomics Node, (INB) at CIPF, Valencia, Spain
    3. CIBER de Enfermedades Raras (CIBERER), Valencia, Spain
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  • Virginia Nunes,

    1. Laboratorio de Genética Molecular, IDIBELL, Departament de Ciències Fisiològiques II, Facultad de Medicina, University of Barcelona, U-730 CIBER de Enfermedades Raras (CIBERER), Barcelona, Spain
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  • Magdalena Ugarte,

    1. Centro de Diagnóstico de Enfermedades Moleculares (CEDEM), Centro de Biología Molecular “Severo Ochoa” CSIC-UAM, Departamento de Biología Molecular, Universidad Autónoma de Madrid, CIBER de Enfermedades Raras (CIBERER), IDIPAZ, Madrid, Spain
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  • Rafael Artuch,

    1. Department of Biochemistry, Hospital Sant Joan de Déu (HSJD), CIBER de Enfermedades Raras (CIBERER), Barcelona, Spain
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    • These authors share senior authorship.

  • Manuel Palacín,

    1. Institute for Research in Biomedicine (IRB Barcelona), Department of Biochemistry and Molecular Biology, Faculty of Biology, University of Barcelona, CIBER de Enfermedades Raras (CIBERER), Barcelona, Spain
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    • These authors share senior authorship.

  • Pilar Rodríguez-Pombo,

    Corresponding author
    1. Centro de Diagnóstico de Enfermedades Moleculares (CEDEM), Centro de Biología Molecular “Severo Ochoa” CSIC-UAM, Departamento de Biología Molecular, Universidad Autónoma de Madrid, CIBER de Enfermedades Raras (CIBERER), IDIPAZ, Madrid, Spain
    • Correspondence to: Pilar Rodríguez-Pombo, Centro de Biología Molecular Severo Ochoa, C/ Nicolás Cabrera Nº #1, Universidad Autónoma Madrid, Madrid 28049, Spain. E-mail: mprodriguez@cbm.csic.es

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    • These authors share senior authorship.

  • Working Group: ( Patricia Alcaide,

    1. Centro de Diagnóstico de Enfermedades Moleculares (CEDEM), Centro de Biología Molecular “Severo Ochoa” CSIC-UAM, Departamento de Biología Molecular, Universidad Autónoma de Madrid, CIBER de Enfermedades Raras (CIBERER), IDIPAZ, Madrid, Spain
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  • Rosa Navarrete,

    1. Centro de Diagnóstico de Enfermedades Moleculares (CEDEM), Centro de Biología Molecular “Severo Ochoa” CSIC-UAM, Departamento de Biología Molecular, Universidad Autónoma de Madrid, CIBER de Enfermedades Raras (CIBERER), IDIPAZ, Madrid, Spain
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  • Paloma Sanz,

    1. Centro de Diagnóstico de Enfermedades Moleculares (CEDEM), Centro de Biología Molecular “Severo Ochoa” CSIC-UAM, Departamento de Biología Molecular, Universidad Autónoma de Madrid, CIBER de Enfermedades Raras (CIBERER), IDIPAZ, Madrid, Spain
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  • Mariona Font-Llitjós,

    1. Functional Genomics Node, (INB) at CIPF, Valencia, Spain
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  • Ma Antonia Vilaseca,

    1. CIBER de Enfermedades Raras (CIBERER), Valencia, Spain
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  • Aida Ormaizabal,

    1. CIBER de Enfermedades Raras (CIBERER), Valencia, Spain
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  • Anna Pristoupilova,

    1. National Center of Genomic Analysis, Barcelona, Spain)
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  • and ) Sergi Beltran Agulló

    1. National Center of Genomic Analysis, Barcelona, Spain)
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  • Contract grant sponsors: Fundación Ramón Areces (CIVP16A1853); Spanish Ministerio de Economia y Competitividad (PI12/02078), (SAF2012-40080-C02-01), (SAF2009-12606-C02-02); Generalitat de Catalunya (SGR2009-1355), (SGR2009-1490); Programa de intensificación de la actividad investigadora (FIS); Fundación Ramon Areces.

  • Communicated by David S. Rosenblatt

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.

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