COX15 – Leigh syndrome

Cytochrome c oxidase assembly protein 15 (COX15) catalyzes the final step in heme A biosynthesis, a critical prosthetic group for mitochondrial complex IV. Leigh syndrome (Leigh syndrome) is a clinically heterogeneous, autosomal recessive neurodegenerative disorder presenting in infancy with psychomotor delay, hypotonia, ataxia, and lactic acidosis. Pathogenic variants in nuclear genes and mitochondrial DNA loci of the respiratory chain have been implicated in Leigh syndrome. COX15 was first described as a Leigh syndrome gene following identification of bi-allelic mutations in patients with isolated complex IV deficiency. Here, we summarize genetic and experimental evidence supporting a causal association between COX15 deficiency and Leigh syndrome phenotypes. Understanding the spectrum of COX15 mutations informs prognostic counseling and targeted biochemical diagnostics.

Biallelic COX15 variants have been reported in four unrelated Leigh syndrome patients (PMID:15863660; PMID:26959537; PMID:32232962). These include canonical splice-site changes such as c.90+1G>A and c.750+1G>T, nonsense alleles like c.452C>G (p.Ser151Ter), and missense variants including c.415C>G (p.Leu139Val) and recurrent c.649C>T (p.Arg217Trp). Inheritance is autosomal recessive, with segregation of homozygous c.649C>T in two affected siblings from a consanguineous pedigree (PMID:32232962). Clinical genotypes correlate with enzyme activity; truncating variants often present with severe neonatal cardiomyopathy, whereas missense changes yield variable neurodegenerative courses. Collectively, this case series demonstrates that COX15 is a bona fide Leigh syndrome gene. Segregation data in one family (two affected offspring) reinforce the pathogenicity of homozygous and compound heterozygous alleles.

Variant spectrum in COX15-related Leigh syndrome encompasses loss-of-function changes that abolish heme A synthesis and missense alterations impacting protein stability or oligomerization. The recurrent c.649C>T (p.Arg217Trp) mutation was identified in three of five reported patients across distinct ethnic backgrounds, indicating a mutational hotspot (PMID:32232962; PMID:12474143). Novel missense c.415C>G (p.Leu139Val) was associated with a milder, slowly progressive phenotype in a 7-year-old child (PMID:26959537). Splice-site variants such as c.90+1G>A and c.750+1G>T produce frameshifts and early termination, correlating with severe neonatal presentations (PMID:15863660). Together, both allelic heterogeneity and recurrent hotspots underscore the need for comprehensive sequencing of COX15 in suspected Leigh syndrome cases.

Functional assays demonstrate that COX15 defects impair heme A production, stalling assembly of cytochrome c oxidase. In patient fibroblasts with compound heterozygous splice (c.447-3G) and missense (c.649C>T (p.Arg217Trp)) alleles, COX activity and fully assembled complex IV were reduced by 50–70%, and heme A levels diminished with accumulation of heme O (PMID:12474143). Lentiviral overexpression of wild-type COX15 in these cells restored heme A content and COX activity, constituting definitive rescue data. Yeast studies of Cox15 reveal that pathogenic variants such as p.Arg217Trp and p.Ser344Pro compromise protein oligomerization and enzymatic function, validating a loss-of-function mechanism (PMID:26940873). Concordant cellular and model organism data support haploinsufficient or null alleles as drivers of disease. No functional studies to date suggest dominant-negative effects.

Clinically, COX15 mutations manifest a spectrum from fatal infantile cardiomyopathy to slowly progressive Leigh syndrome without cardiac involvement. The long-surviving adult patient described by Mattevi et al. exhibited mild muscle COX deficiency and preserved assembly in fibroblasts, contrasting with rapidly fatal neonatal cases (PMID:15863660). Neurological features include developmental regression, hypotonia, tremor, nystagmus, pyramidal signs, and pseudobulbar paralysis with variable onset ages. Some patients present with normal lactate levels and imaging, complicating clinical recognition (PMID:26959537). This phenotypic variability underscores the importance of molecular testing in unexplained COX deficiency. No studies have refuted the COX15–Leigh syndrome link or implicated alternative phenotypes.

In summary, genetic and functional data robustly support a gene-disease association between COX15 and autosomal recessive Leigh syndrome. Diagnostic screening of COX15 should include sequencing of coding regions and splice junctions, particularly in patients with complex IV deficiency and neurological signs. Identification of recurrent hotspots facilitates efficient variant interpretation. Functional complementation assays remain the gold standard for variant validation. Early molecular diagnosis enables informed genetic counseling, prognostication, and potential enrollment in emerging therapeutic trials. Key Take-home: Biallelic loss-of-function or missense COX15 variants cause Leigh syndrome by impeding heme A biosynthesis and complex IV assembly, warranting COX15 analysis in relevant clinical settings.

References

• Journal of medical genetics • 2005 • Novel mutations in COX15 in a long surviving Leigh syndrome patient with cytochrome c oxidase deficiency. PMID:15863660
• Journal of pediatric endocrinology & metabolism : JPEM • 2016 • Leigh syndrome associated with a novel mutation in the COX15 gene. PMID:26959537
• American journal of medical genetics. Part A • 2020 • Phenotypic variability and mutation hotspot in COX15-related Leigh syndrome. PMID:32232962
• American journal of human genetics • 2003 • Mutations in COX15 produce a defect in the mitochondrial heme biosynthetic pathway, causing early-onset fatal hypertrophic cardiomyopathy. PMID:12474143
• The Journal of biological chemistry • 2016 • Analysis of Oligomerization Properties of Heme a Synthase Provides Insights into Its Function in Eukaryotes. PMID:26940873

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