The novel mutation p.Asp251Asn in the β-subunit of succinate-CoA ligase causes encephalomyopathy and elevated succinylcarnitine

Abstract

SUCLA2 is one of several nuclear-encoded genes that can cause encephalomyopathy accompanied by mitochondrial DNA depletion. The disorder usually manifests in early childhood and leads to early death. The gene encodes one of the subunits of succinyl-CoA synthase, the enzyme that catalyzes the reversible conversion of substrates succinyl-CoA and ADP to products succinate and ATP in the tricarboxylic acid pathway. Thirty-two individuals harboring mutations in SUCLA2 have so far been reported, and five different mutations were observed among these individuals. Here we report identification of a novel mutation in SUCLA2 in two cousins affected with encephalomyopathy. The novel mutation causes p.Asp251Asn; the affected amino acid is likely positioned within the ATP-grasp domain of the encoded protein. As previously reported in other patients, we did not observe elevation of methylmalonic acid, the biochemical hallmark of patients with mutations in SUCLA2. We instead found elevated levels of succinylcarnitine.

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

“…The patients, who were examined, had a respiratory chain SUCLA2 point mutation and 13q14 deletion S Matilainen et al defect and depletion of mtDNA. [6][7][8][9][10] Our two Finnish patients became symptomatic at the age of 5-6 months, similar to other reported patients, but showed clearly slower progression of the disease: at the current age of 9 and 20, they are able to walk with a walker, go to school and, despite a hearing deficit and inability to speak, are able to communicate using signs and gestures. The MRI findings of patient 1 have not progressed between the age of 2 and a half years and 7 years of age.…”

“…Previously, three patients have been reported to have normal levels of MMA in urine. 9,10 Furthermore, the muscle mtDNA copy number in patient 1 did not fulfill the criteria of mtDNA depletion. 18 These data establish that patients with normal or transiently increased levels of MMA in urine and a normal amount of mtDNA may have SUCLA2 mutations.…”

“…3,6 Over 20 patients and five different mutations in SUCLA2 have been described. [6][7][8][9][10] We report here molecular basis of mitochondrial encephalomyopathy, also combined with bilateral retinoblastoma, in patients with clinical symptoms or signs previously described in association with SUCLA2 mutations: encephalomyopathy with hearing deficit and methylmalonic aciduria.…”

“…All Faroese patients carried the mutation c.534 þ 1G4A in intron 4, 7,8 which led to multiple exon skipping, resulting in complete absence of functional protein. 8 Two Italian patients had a homozygous Arg284Cys change, an Italian/ Romanian patient was heterozygous for Arg284Cys and Gly118Arg 8 and two Iranian cousins were homozygous for a mutation encoding Asp251, 10 an interaction partner of Arg284. Arg284 and Asp251 form one of the contacts critical for folding of the b-subunit and the stability of the dimer (Figure 3c) and mutations Arg284Cys and Asp251Asn are predicted to result in a less stable b-subunit.…”

Fatty Acid Chain Elongation in Palmitate-perfused Working Rat Heart

“…If this was the case, then the stable isotope enrichment in malonylcarnitine should have been identical to that in malonyl-CoA. This expectation is based on increased excretion of succinylcarnitine and methylmalonylcarnitine in patients with succinate-CoA ligase and methylmalonyl-CoA mutase/epimerase deficiency, enzymes exclusively localized in the mitochondrial matrix (52)(53)(54)(55). Therefore, mitochondria must have the capability to catalyze the reversible transesterification between dicarboxylylCoAs and carnitine, brought about either by CAT or an acylcarnitine transferase yet to be identified.…”