SCO2 – Leigh syndrome

SCO2 encodes a mitochondrial copper‐binding chaperone essential for the assembly of cytochrome c oxidase (COX). Biallelic loss‐of‐function variants in SCO2 cause autosomal recessive cytochrome c oxidase deficiency presenting as Leigh syndrome, a subacute necrotizing encephalopathy PMID:10545952.

1 Assess Clinical Validity

Based on at least 29 unrelated probands with consistent autosomal recessive inheritance (26 in a neonatal cohort and 3 in an early multi‐family series) and concordant segregation and functional studies, the gene–disease association is classified as Definitive.

2 Genetic Evidence

Inheritance is autosomal recessive. Compound heterozygous and homozygous SCO2 variants segregate with disease; two siblings in one family share a nonsense allele PMID:10749987. A total of 29 probands have been reported (26 neonates with fatal infantile cardioencephalomyopathy at presentation and Leigh syndrome on MRI PMID:20159436; 3 unrelated infants in the inaugural multi‐patient study PMID:10545952). The variant spectrum includes frameshift (e.g., c.327_328del (p.His109fs)), nonsense (c.268C>T (p.Arg90Ter), c.157C>T (p.Gln53Ter)), and missense (c.674C>T (p.Ser225Phe), hotspot c.418G>A (p.Glu140Lys)) changes.

3 Functional / Experimental Evidence

Patient muscle and fibroblast studies demonstrate absent or severely reduced COX activity, with immunohistochemistry showing marked loss of mitochondrial‐encoded COX subunits II/III PMID:20159436. Recombinant E140K and S225F proteins exhibit altered conformation and impaired copper binding in vitro PMID:14972329. COX activity in patient myoblasts is fully rescued by copper‐histidine supplementation and by retroviral SCO2 expression PMID:11751685.

4 Conflicting Evidence

Heterozygosity for pathogenic SCO2 alleles, including E140K, does not predispose to high‐grade myopia or other phenotypes in carriers PMID:26427993.

5 Integration & Conclusion

Collectively, robust genetic evidence from >29 probands with autosomal recessive SCO2 mutations, segregation in families, extensive functional concordance in cellular and biochemical assays, and successful rescue experiments establish a Definitive association between SCO2 and Leigh syndrome. SCO2 testing is clinically useful for early diagnosis of neonatal encephalopathy with cardiomyopathy and lactic acidosis, guiding potential copper‐based therapies.

Key Take-home: SCO2 mutations cause autosomal recessive Leigh syndrome via COX assembly failure; functional rescue by copper highlights therapeutic avenues.

References

• Nature Genetics • 1999 • Fatal infantile cardioencephalomyopathy with COX deficiency and mutations in SCO2, a COX assembly gene. PMID:10545952
• Pediatric Neurology • 2010 • A novel mutation in the SCO2 gene in a neonate with early-onset cardioencephalomyopathy. PMID:20159436
• Human Molecular Genetics • 2004 • Human recombinant mutated forms of the mitochondrial COX assembly Sco2 protein differ from wild-type in physical state and copper binding capacity. PMID:14972329
• Human Molecular Genetics • 2001 • Cytochrome c oxidase deficiency due to mutations in SCO2, encoding a mitochondrial copper-binding protein, is rescued by copper in human myoblasts. PMID:11751685
• JIMD Reports • 2016 • No Evidence for Association of SCO2 Heterozygosity with High-Grade Myopia or Other Diseases with Possible Mitochondrial Dysfunction. PMID:26427993

Evidence Based Scoring (AI generated)