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Published on: March 24, 2019
The severity of phenotype linked to SUCLG1 mutations could be correlated with residual amount of SUCLG1 protein
C Rouzier1, S Le Guédard-Méreuze, K Fragaki
1Department of Medical Genetics, Archet 2 Hospital, CHU of Nice France.
Background:
Succinate-CoA ligase deficiency is responsible for encephalomyopathy with mitochondrial DNA depletion and mild methylmalonic aciduria. Mutations in SUCLA2, the gene encoding a β subunit of succinate-CoA ligase, have been reported in 17 patients until now. Mutations in SUCLG1, encoding the α subunit of the enzyme, have been described in two pedigrees only.
Methods And Findings:
In this study, two unrelated patients harbouring three novel pathogenic mutations in SUCLG1 were reported. The first patient had a severe disease at birth. He was compound heterozygous for a missense mutation (p.Pro170Arg) and a c.97+3G>C mutation, which leads to the complete skipping of exon 1 in a minigene expression system. The involvement of SUCLG1 was confirmed by western blot analysis, which showed absence of SUCLG1 protein in fibroblasts. The second patient has a milder phenotype, similar to that of patients with SUCLA2 mutations, and is still alive at 12 years of age. Western blot analysis showed some residual SUCLG1 protein in patient's fibroblasts.
Conclusions:
Our results suggest that SUCLG1 mutations that lead to complete absence of SUCLG1 protein are responsible for a very severe disorder with antenatal manifestations, whereas a SUCLA2-like phenotype is found in patients with residual SUCLG1 protein. Furthermore, it is shown that in the absence of SUCLG1 protein, no SUCLA2 protein is found in fibroblasts by western blot analysis. This result is consistent with a degradation of SUCLA2 when its heterodimer partner, SUCLG1, is absent.
Insights
Succinate-CoA ligase deficiency, caused by SUCLG1 mutations, leads to severe disease when the protein is absent. Residual SUCLG1 protein results in a milder, SUCLA2-like phenotype in patients.
Area of Science:
- Biochemistry
- Genetics
- Mitochondrial Biology
Background:
- Succinate-CoA ligase deficiency causes encephalomyopathy, mitochondrial DNA depletion, and methylmalonic aciduria.
- Mutations in SUCLA2 (β subunit) reported in 17 patients; SUCLG1 (α subunit) mutations in only two pedigrees.
Observation:
- Reported three novel pathogenic SUCLG1 mutations in two unrelated patients.
- Patient 1: Severe neonatal disease, compound heterozygous for p.Pro170Arg and c.97+3G>C mutations, with absent SUCLG1 protein.
- Patient 2: Milder, SUCLA2-like phenotype, alive at 12 years, with residual SUCLG1 protein.
Findings:
- Absence of SUCLG1 protein confirmed by western blot in patient fibroblasts.
- Residual SUCLG1 protein detected in the milder phenotype patient's fibroblasts.
- SUCLA2 protein is degraded in fibroblasts lacking SUCLG1 protein, indicating partner dependency.
Implications:
- SUCLG1 mutations causing complete protein absence lead to severe antenatal disease.
- Residual SUCLG1 protein is associated with a SUCLA2-like phenotype.
- SUCLG1 absence causes SUCLA2 degradation, highlighting the enzyme's heterodimeric structure and function.
