SUCLG1 – Mitochondrial DNA Depletion Syndrome 9

Succinate‐CoA ligase α‐subunit deficiency due to biallelic SUCLG1 variants causes an autosomal recessive mitochondrial DNA depletion syndrome characterized by early‐onset hypotonia, lactic acidosis and sensorineural hearing loss. The nuclear gene SUCLG1 encodes the α subunit of the succinate‐CoA ligase heterodimer essential for mtDNA stability and integrity, and is definitively linked to Mitochondrial DNA Depletion Syndrome 9.

Genetic Evidence

Seven unrelated probands from six families have been reported with biallelic SUCLG1 variants presenting with mitochondrial DNA depletion, encephalomyopathy, lactic acidosis and mild methylmalonic aciduria in an autosomal recessive pattern, including a Chinese infant carrying c.601A>G (p.Arg201Gly) and c.871G>C (p.Ala291Pro) (PMID:35762302). The variant spectrum comprises missense, nonsense, splice‐site and frameshift alleles without apparent founder mutations.

Functional Evidence

In vitro assays in patient fibroblasts demonstrate absent or markedly reduced SUCLG1 protein leading to secondary depletion of SUCLA2 and SUCLG2 subunits and ≈68% reduction in mtDNA content (PMID:20693550). Rescue of SCS enzyme activity, mtDNA levels and cellular respiration defects upon wild-type SUCLG1 expression confirms a loss-of-function mechanism (PMID:27484306). Minigene splicing assays and western blots correlate absent protein with more severe antenatal phenotypes and residual protein with milder, SUCLA2‐like presentations.

Mechanism and Clinical Implications

Biallelic loss-of-function variants in SUCLG1 disrupt succinate‐CoA ligase activity, impair mitochondrial substrate-level phosphorylation and destabilize mtDNA maintenance, driving the encephalomyopathic and metabolic features of MTDPS9. The concordant genetic and experimental data support strong clinical validity and indicate that SUCLG1 sequencing is essential for molecular diagnosis, genetic counseling and tailored management of affected infants.

Key Take-home: Autosomal recessive SUCLG1 deficiency is a well-established cause of mitochondrial DNA depletion syndrome 9; early genetic testing enables precise diagnosis and informs carrier screening and therapeutic strategies.

References

• Molecular genetics & genomic medicine • 2022 • Novel compound heterozygous SUCLG1 variants may contribute to mitochondria DNA depletion syndrome-9. PMID:35762302
• Journal of medical genetics • 2010 • The severity of phenotype linked to SUCLG1 mutations could be correlated with residual amount of SUCLG1 protein. PMID:20693550
• Molecular genetics and metabolism • 2016 • Expanding the phenotypic spectrum of Succinyl-CoA ligase deficiency through functional validation of a new SUCLG1 variant. PMID:27484306

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