title: Mitochondrial encephalomyopathy and retinoblastoma explained by compound heterozygosity of SUCLA2 point mutation and 13q14 deletion.
abstract: Mutations in SUCLA2, encoding the ß-subunit of succinyl-CoA synthetase of Krebs cycle, are one cause of mitochondrial DNA depletion syndrome. Patients have been reported to have severe progressive childhood-onset encephalomyopathy, and methylmalonic aciduria, often leading to death in childhood. We studied two families, with children manifesting with slowly progressive mitochondrial encephalomyopathy, hearing impairment and transient methylmalonic aciduria, without mtDNA depletion. The other family also showed dominant inheritance of bilateral retinoblastoma, which coexisted with mitochondrial encephalomyopathy in one patient. We found a variant in SUCLA2 leading to Asp333Gly change, homozygous in one patient and compound heterozygous in one. The latter patient also carried a deletion of 13q14 of the other allele, discovered with molecular karyotyping. The deletion spanned both SUCLA2 and RB1 gene regions, leading to manifestation of both mitochondrial disease and retinoblastoma. We made a homology model for human succinyl-CoA synthetase and used it for structure-function analysis of all reported pathogenic mutations in SUCLA2. On the basis of our model, all previously described mutations were predicted to result in decreased amounts of incorrectly assembled protein or disruption of ADP phosphorylation, explaining the severe early lethal manifestations. However, the Asp333Gly change was predicted to reduce the activity of the otherwise functional enzyme. On the basis of our findings, SUCLA2 mutations should be analyzed in patients with slowly progressive encephalomyopathy, even in the absence of methylmalonic aciduria or mitochondrial DNA depletion. In addition, an encephalomyopathy in a patient with retinoblastoma suggests mutations affecting SUCLA2.
authors.affiliation: Research Programs Unit, Molecular Neurology, Biomedicum-Helsinki, University of Helsinki, Helsinki, Finland.
authors.forename: Sanna
authors.initials: S
authors.lastname: Matilainen
authors.affiliation: 1] Research Programs Unit, Molecular Neurology, Biomedicum-Helsinki, University of Helsinki, Helsinki, Finland [2] Department of Child Neurology, Children's hospital, Helsinki University Central Hospital and University of Helsinki, Helsinki, Finland.
authors.forename: Pirjo
authors.initials: P
authors.lastname: Isohanni
authors.affiliation: Research Programs Unit, Molecular Neurology, Biomedicum-Helsinki, University of Helsinki, Helsinki, Finland.
authors.forename: Liliya
authors.initials: L
authors.lastname: Euro
authors.affiliation: Department of Child Neurology, Children's hospital, Helsinki University Central Hospital and University of Helsinki, Helsinki, Finland.
authors.forename: Tuula
authors.initials: T
authors.lastname: Lönnqvist
authors.affiliation: Department of Child Neurology, Children's hospital, Helsinki University Central Hospital and University of Helsinki, Helsinki, Finland.
authors.forename: Helena
authors.initials: H
authors.lastname: Pihko
authors.affiliation: Department of Ophthalmology, Helsinki University Central Hospital, Helsinki, Finland.
authors.forename: Tero
authors.initials: T
authors.lastname: Kivelä
authors.affiliation: Department of Pathology, Haartman Institute and HUSLab, University of Helsinki, Helsinki, Finland.
authors.forename: Sakari
authors.initials: S
authors.lastname: Knuutila
authors.affiliation: 1] Research Programs Unit, Molecular Neurology, Biomedicum-Helsinki, University of Helsinki, Helsinki, Finland [2] Department of Neurology, Helsinki University Central Hospital, Helsinki, Finland [3] Neuroscience center, University of Helsinki, Helsinki, Finland.
authors.forename: Anu
authors.initials: A
authors.lastname: Suomalainen
mesh_terms: D000293:Adolescent; D001921:Brain / Q000473:pathology; D002872:Chromosome Deletion; D002882:Chromosomes, Human, Pair 13; D055028:Comparative Genomic Hybridization; D017809:Fatal Outcome; D005787:Gene Frequency; D006579:Heterozygote; D006801:Humans; D007223:Infant; D008279:Magnetic Resonance Imaging; D008297:Male; D017237:Mitochondrial Encephalomyopathies / Q000150:complications / Q000175:diagnosis / Q000235:genetics*; D008958:Models, Molecular; D010375:Pedigree; D017354:Point Mutation; D011487:Protein Conformation; D012175:Retinoblastoma / Q000150:complications / Q000175:diagnosis / Q000235:genetics*; D017422:Sequence Analysis, DNA; D013329:Structure-Activity Relationship; D013389:Succinate-CoA Ligases / Q000737:chemistry / Q000235:genetics*
chemical_list: D013389:Succinate-CoA Ligases; C518788:SUCLA2 protein, human