SCO1 – Mitochondrial Disease

SCO1 encodes a mitochondrial copper-binding assembly factor essential for cytochrome c oxidase (COX) biogenesis and cellular energy metabolism. Pathogenic variants in SCO1 cause an autosomal recessive mitochondrial disease characterized by neonatal metabolic failure and hypoglycemia (Gene Symbol, Disease Name).

Autosomal recessive inheritance is supported by compound heterozygous and homozygous SCO1 variants in four unrelated probands with early-onset lactic acidosis and hypoglycemia. A homozygous in-frame deletion Gly106del presented with neonatal hypoglycemia and severe chronic lactate acidosis in a sibship (n=2) (PMID:31352446). Compound heterozygous frameshift c.261del (p.Ser88fs) and missense c.521C>T (p.Pro174Leu) segregated with isolated COX deficiency and hepatic failure in two siblings (PMID:11013136). Another patient carried p.Val93Ter and p.Met294Val without cardiac involvement but with reduced COX activity (PMID:23878101).

The variant spectrum encompasses loss-of-function alleles: frameshift c.261del (p.Ser88fs), c.551del (p.Val184fs) (PMID:23878101), splice c.364_364+1del (PMID:23878101), and nonsense p.Val93Ter (PMID:23878101); and missense alleles p.Pro174Leu (PMID:11013136), p.Gly132Ser (PMID:19295170), and p.Met294Val (PMID:23878101).

Next-generation sequencing in large neonatal cohorts identified SCO1 mutations in WES/TES panels, confirming its role across diverse presentations of mitochondrial disease (PMID:33629572, PMID:22231385).

Functional assays in patient fibroblasts demonstrate severe COX deficiency and copper depletion, partially rescued by allele-specific SCO1 overexpression (PMID:23878101, PMID:16520371). Yeast and cellular models confirm SCO1’s essential role in CuA site metallation of COX subunit II, with patient mutations impairing chaperone activity and complex assembly (PMID:10854440, PMID:15229189).

However, a survey of SCO1 in 30 patients with isolated COX deficiency found no pathogenic variants, indicating locus heterogeneity and the need for comprehensive genetic testing (PMID:11027508).

Integration of genetic and experimental data supports a haploinsufficiency mechanism whereby defective copper metallation leads to COX assembly failure and neonatal mitochondrial disease. Early implementation of SCO1 sequencing in neonates with lactic acidosis and hypoglycemia enables rapid diagnosis, prognostic prediction, and tailored management.

Key Take-home: SCO1 mutations define an autosomal recessive mitochondrial disease with neonatal hypoglycemia and COX deficiency; targeted genetic testing is critical for early diagnosis and intervention.

References

• Neonatology • 2019 • Mitochondrial Disease Caused by a Novel Homozygous Mutation (Gly106del) in the SCO1 Gene. PMID:31352446
• American Journal of Human Genetics • 2000 • Mutations of the SCO1 gene in mitochondrial cytochrome c oxidase deficiency with neonatal-onset hepatic failure and encephalopathy. PMID:11013136
• Human Mutation • 2013 • Novel mutations in SCO1 as a cause of fatal infantile encephalopathy and lactic acidosis. PMID:23878101
• The American Journal of Pathology • 2010 • Unexpected vascular enrichment of SCO1 over SCO2 in mammalian tissues: implications for human mitochondrial disease. PMID:20864674
• Journal of inherited metabolic disease • 2012 • Neonatal onset of mitochondrial disorders in 129 patients: clinical and laboratory characteristics and a new approach to diagnosis. PMID:22231385
• Journal of pediatric endocrinology & metabolism • 2021 • The utility of next-generation sequencing technologies in diagnosis of Mendelian mitochondrial diseases and reflections on clinical spectrum. PMID:33629572
• Biochemical and Biophysical Research Communications • 2000 • Characterization of human SCO1 and COX17 genes in mitochondrial cytochrome-c-oxidase deficiency. PMID:11027508
• The Journal of Biological Chemistry • 2000 • A human SCO2 mutation helps define the role of Sco1p in the cytochrome oxidase assembly pathway. PMID:10854440
• Human Molecular Genetics • 2004 • Human SCO1 and SCO2 have independent, cooperative functions in copper delivery to cytochrome c oxidase. PMID:15229189
• The Journal of Biological Chemistry • 2006 • The P174L mutation in human Sco1 severely compromises Cox17-dependent metallation but does not impair copper binding. PMID:16520371

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