Mitochondrial encephalomyopathy and retinoblastoma explained by compound heterozygosity of SUCLA2 point mutation and 13q14 deletion

Abstract

Mutations in SUCLA2, encoding the -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.

Two transgenic mouse models for β-subunit components of succinate-CoA ligase yielding pleiotropic metabolic alterations

“…To date, 51 patients have been reported with SUCLA2 deficiency [6,7,20,24,29,41,44,46,49,50,52,54], and 21 patients with SUCLG1 deficiency, due to different mutations [7]. Patients with SUCLG1 mutations may have an extremely severe phenotype with antenatal manifestations of the disorder, severe acidosis with lactic aciduria in the first day of life and death within 2–4 days [53] or a phenotype similar to those of patients with SUCLA2 mutations.…”

Findings made in gene panel to whole genome sequencing: data, knowledge, ethics – and consequences?

“…However, trios of unaffected parents and an affected child are commonly analyzed for homozygous or compound heterozygous mutations just occurring in the offspring [94,95]. Further, sequencing of distantly related affected individuals from larger pedigrees is applied to uncover autosomal dominant events.…”

SUCLA2 mutations cause global protein succinylation contributing to the pathomechanism of a hereditary mitochondrial disease

“…SCL deficiency is a mitochondrial DNA (mtDNA) depletion syndrome with methylmalonic aciduria (OMIM#612073 and #245400) that manifests with a Leigh/Leigh-like encephalomyopathy [22][23][24] . Altogether, more than 20 patients with mutations in the gene encoding the α-subunit, SUCLG1, and 50 patients with mutations of the gene encoding the ATP-specific β-subunit, SUCLA2, have been reported.…”