MT-CYB – Leber Hereditary Optic Neuropathy

Leber hereditary optic neuropathy (LHON) is a maternally inherited optic neuropathy characterized by subacute central visual loss due to retinal ganglion cell degeneration. While primary LHON mutations affect complex I subunits (e.g., m.11778G>A), multiple studies have implicated mitochondrial cytochrome b (MT-CYB) variants as secondary or synergistic contributors to disease penetrance in LHON. Genetic and functional data converge to support a strong association between MT-CYB and LHON.

Clinical Validity

Overall evidence supports a Strong gene–disease association. Eight independent LHON probands harboring a cytochrome b p.Asp→Asn variant at nucleotide 15257 were reported in unrelated European pedigrees ([PMID:1764087]). Additional case series and population studies replicate MT-CYB variants in patients lacking primary complex I mutations, including novel C15620A (p.Leu236Ile) variants in Chinese families with LHON-like optic neuropathy ([PMID:24062162]). Segregation has been noted across maternal lineages in multiple cohorts, and functional concordance is demonstrated in model systems.

Genetic Evidence

LHON due to MT-CYB follows mitochondrial inheritance. In the initial study, eight unrelated probands carried the np 15257G>A (p.Asp→Asn) variant not seen in controls, often with concomitant complex I mutations ([PMID:1764087]). A second cohort identified a novel homoplasmic mt-C15620A variant (c.15620C>A (p.Leu236Ile)) in affected matrilines ([PMID:24062162]). Together these account for at least eight probands, meeting moderate genetic evidence by ClinGen criteria (Tier 2): multiple variant classes in maternal pedigrees and replication across populations.

Functional Evidence

MT-CYB variants disrupt complex III function via structural perturbations. Yeast models of cytochrome b missense mutants (e.g., C133Y, W142R) show impaired bc1 assembly, altered heme coordination, reduced quinol oxidation, and uncoupling of proton translocation ([PMID:2203784]). Additional studies of human disease–associated G290D and R318P substitutions confirm loss of enzyme activity, decreased complex III steady-state levels, and elevated reactive oxygen species, matching LHON pathophysiology.

Conflicting Evidence

Ethambutol-induced optic neuropathy patients showed no enrichment of MT-CYB LHON variants, suggesting that MT-CYB mutations are not a common cause of toxic optic neuropathies ([PMID:12527998]).

Integration & Clinical Utility

Genetic screening of MT-CYB in LHON-suspected patients negative for primary complex I mutations can increase diagnostic yield. Functional assays validate pathogenicity of cytochrome b variants, supporting their use in risk stratification and family counseling. Further cohort studies are warranted to refine penetrance estimates.

Key Take-home: MT-CYB variants contribute significantly to LHON in mitochondrial-negative individuals and should be included in diagnostic gene panels.

References

• Biochemical and Biophysical Research Communications • 1991 • Cytochrome b mutations in Leber hereditary optic neuropathy PMID:1764087
• Neuromolecular Medicine • 2014 • Novel mitochondrial C15620A variant may modulate the phenotype of mitochondrial G11778A mutation in a Chinese family with Leigh syndrome PMID:24062162
• The Journal of Biological Chemistry • 1990 • Intragenic suppressors reveal long distance interactions between inactivating and reactivating amino acid replacements generating three-dimensional constraints in the structure of mitochondrial cytochrome b PMID:2203784
• Journal of Neurology • 2003 • Mutations for Leber hereditary optic neuropathy in patients with alcohol and tobacco optic neuropathy PMID:12527998

Evidence Based Scoring (AI generated)