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Mutated SUCLG1 causes mislocalization of SUCLG2 protein, morphological alterations of mitochondria and an early-onset severe neurometabolic disorder.
Chinopoulos, Christos; Batzios, Spyros; van den Heuvel, Lambertus P; Rodenburg, Richard; Smeets, Roel; Waterham, Hans R; Turkenburg, Marjolein; Ruiter, Jos P; Wanders, Ronald J A; Doczi, Judit; Horvath, Gergo; Dobolyi, Arpad; Vargiami, Euthymia; Wevers, Ron A; Zafeiriou, Dimitrios.
Afiliación
  • Chinopoulos C; Department of Medical Biochemistry, Semmelweis University, Budapest, Hungary.
  • Batzios S; 1st Department of Pediatrics, "Hippokratio" General Hospital, Aristotle University, Thessaloniki, Greece; Department of Paediatric Metabolic Medicine, Great Ormond Street Hospital, London, UK.
  • van den Heuvel LP; Department of Pediatrics, Radboud University Medical Centre, Nijmegen, The Netherlands; Translational Metabolic Laboratory, Department Laboratory Medicine, Radboud University Medical Centre, Nijmegen, The Netherlands.
  • Rodenburg R; Department of Pediatrics, Radboud University Medical Centre, Nijmegen, The Netherlands; Translational Metabolic Laboratory, Department Laboratory Medicine, Radboud University Medical Centre, Nijmegen, The Netherlands.
  • Smeets R; Translational Metabolic Laboratory, Department Laboratory Medicine, Radboud University Medical Centre, Nijmegen, The Netherlands.
  • Waterham HR; Laboratory Genetic Metabolic Diseases, Amsterdam University Medical Centers, University of Amsterdam, The Netherlands.
  • Turkenburg M; Laboratory Genetic Metabolic Diseases, Amsterdam University Medical Centers, University of Amsterdam, The Netherlands.
  • Ruiter JP; Laboratory Genetic Metabolic Diseases, Amsterdam University Medical Centers, University of Amsterdam, The Netherlands.
  • Wanders RJA; Laboratory Genetic Metabolic Diseases, Amsterdam University Medical Centers, University of Amsterdam, The Netherlands.
  • Doczi J; Department of Medical Biochemistry, Semmelweis University, Budapest, Hungary.
  • Horvath G; Department of Medical Biochemistry, Semmelweis University, Budapest, Hungary.
  • Dobolyi A; MTA-ELTE Laboratory of Molecular and Systems Neurobiology, Department of Physiology and Neurobiology, Hungarian Academy of Sciences, Eotvos Lorand University, Budapest, Hungary; Department of Anatomy, Histology and Embryology, Semmelweis University, Budapest, Hungary.
  • Vargiami E; 1st Department of Pediatrics, "Hippokratio" General Hospital, Aristotle University, Thessaloniki, Greece.
  • Wevers RA; Translational Metabolic Laboratory, Department Laboratory Medicine, Radboud University Medical Centre, Nijmegen, The Netherlands. Electronic address: ron.wevers@radboudumc.nl.
  • Zafeiriou D; 1st Department of Pediatrics, "Hippokratio" General Hospital, Aristotle University, Thessaloniki, Greece. Electronic address: zafeiriou@icloud.com.
Mol Genet Metab ; 126(1): 43-52, 2019 01.
Article en En | MEDLINE | ID: mdl-30470562
Succinate-CoA ligase (SUCL) is a heterodimer consisting of an alpha subunit encoded by SUCLG1, and a beta subunit encoded by either SUCLA2 or SUCLG2 catalyzing an ATP- or GTP-forming reaction, respectively, in the mitochondrial matrix. The deficiency of this enzyme represents an encephalomyopathic form of mtDNA depletion syndromes. We describe the fatal clinical course of a female patient with a pathogenic mutation in SUCLG1 (c.626C > A, p.Ala209Glu) heterozygous at the genomic DNA level, but homozygous at the transcriptional level. The patient exhibited early-onset neurometabolic abnormality culminating in severe brain atrophy and dystonia leading to death by the age of 3.5 years. Urine and plasma metabolite profiling was consistent with SUCL deficiency which was confirmed by enzyme analysis and lack of mitochondrial substrate-level phosphorylation (mSLP) in skin fibroblasts. Oxygen consumption- but not extracellular acidification rates were altered only when using glutamine as a substrate, and this was associated with mild mtDNA depletion and no changes in ETC activities. Immunoblot analysis revealed no detectable levels of SUCLG1, while SUCLA2 and SUCLG2 protein expressions were largely reduced. Confocal imaging of triple immunocytochemistry of skin fibroblasts showed that SUCLG2 co-localized only partially with the mitochondrial network which otherwise exhibited an increase in fragmentation compared to control cells. Our results outline the catastrophic consequences of the mutated SUCLG1 leading to strongly reduced SUCL activity, mSLP impairment, mislocalization of SUCLG2, morphological alterations in mitochondria and clinically to a severe neurometabolic disease, but in the absence of changes in mtDNA levels or respiratory complex activities.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Succinato-CoA Ligasas / Enfermedades Mitocondriales / Mitocondrias / Mutación Tipo de estudio: Etiology_studies Límite: Child, preschool / Female / Humans Idioma: En Revista: Mol Genet Metab Asunto de la revista: BIOLOGIA MOLECULAR / BIOQUIMICA / METABOLISMO Año: 2019 Tipo del documento: Article País de afiliación: Hungria Pais de publicación: Estados Unidos
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Succinato-CoA Ligasas / Enfermedades Mitocondriales / Mitocondrias / Mutación Tipo de estudio: Etiology_studies Límite: Child, preschool / Female / Humans Idioma: En Revista: Mol Genet Metab Asunto de la revista: BIOLOGIA MOLECULAR / BIOQUIMICA / METABOLISMO Año: 2019 Tipo del documento: Article País de afiliación: Hungria Pais de publicación: Estados Unidos