Variant Synonymizer: Platform to identify mutations defined in different ways is available now!

VarSy

Over 2,000 gene–disease validation summaries are now available—no login required!

Browse Summaries

COX5A – Cytochrome-c Oxidase Deficiency

Recessive variants in COX5A, encoding subunit Va of cytochrome c oxidase (complex IV), have been linked to infantile‐onset cytochrome-c oxidase deficiency (Cytochrome-c Oxidase Deficiency). A homozygous missense variant, c.266T>G (p.Ile89Ser), was identified in a family with two affected siblings exhibiting lactic acidosis, failure to thrive and reduced COX activity (PMID:35246835). In a separate newborn case, Western blot demonstrated selective depletion of subunits V and VI and NADH:cytochrome c oxidoreductase activity was preserved, while electron microscopy revealed severe myofibre Z-band disruption and mitochondrial cristae malformation (PMID:2175684). Immunohistochemical analysis of muscle from additional COX-deficient patients revealed selective loss of nuclear-encoded subunits, including Va, in a subset of cases, supporting nuclear gene involvement (PMID:10686181).

Mechanistically, loss of COX5A leads to defective complex IV assembly, proteolytic degradation of F-actin and profound ultrastructural mitochondrial alterations. Concordant findings across Western blot, immunostaining and ultrastructural studies substantiate a loss-of-function mechanism. No conflicting reports have been documented to date. Key take-home: COX5A should be included in genetic testing for autosomal recessive cytochrome-c oxidase deficiency presenting with hypotonia and myopathy in infancy.

References

  • Clinica chimica acta; international journal of clinical chemistry • 1990 • Cytochrome oxidase deficiency affecting the structure of the myofibre and the shape of mitochondrial cristae membrane. PMID:2175684
  • Brain : a journal of neurology • 2000 • Cytochrome oxidase immunohistochemistry: clues for genetic mechanisms. PMID:10686181
  • Clinical Genetics • 2022 • A novel homozygous variant in COX5A causes an attenuated phenotype with failure to thrive, lactic acidosis, hypoglycemia, and short stature. PMID:35246835

Evidence Based Scoring (AI generated)

Gene–Disease Association

Limited

Biallelic COX5A variant reported in one family (2 affected siblings)([PMID:35246835]); protein depletion and ultrastructural mitochondrial abnormalities detected in single case([PMID:2175684]); immunohistochemical patterns support nuclear subunit involvement([PMID:10686181]).

Genetic Evidence

Limited

Recessive c.266T>G (p.Ile89Ser) identified in a single family (2 sibs) with enzyme deficiency and reduced COX5A protein([PMID:35246835]).

Functional Evidence

Moderate

Western blot confirmed decreased COX5A levels([PMID:2175684]), EM showed mitochondrial and myofibre structural defects, and immunohistochemistry in cohorts demonstrated selective COX subunit loss([PMID:2175684],[PMID:10686181]).