The molecular basis of human complex I deficiency

Area of Science:

• Biochemistry
• Genetics
• Metabolic Disorders

Background:

• Oxidative phosphorylation (OXPHOS) disorders are the most frequent inborn errors of metabolism, with a birth prevalence of approximately 1/5,000.
• Complex I deficiency is the most common OXPHOS disorder, presenting with diverse clinical symptoms including muscle weakness, developmental issues, and seizures.

Purpose of the Study:

• To review and consolidate information on nuclear gene mutations causing isolated complex I deficiency.
• To highlight the genetic heterogeneity and challenges in molecular diagnosis for complex I deficiency.

Main Methods:

• Comprehensive literature survey to identify patients with isolated complex I deficiency and nuclear gene mutations.
• Analysis of reported pathogenic mutations in nuclear-encoded complex I subunits and assembly factors.

Main Results:

• Identified 149 patients with isolated complex I deficiency linked to nuclear gene mutations.
• Documented 115 distinct pathogenic mutations across 22 nuclear genes, revealing significant allelic and locus heterogeneity.
• Observed different mutation types (missense vs. null) predominating in specific gene categories (core subunits/assembly factors vs. supernumerary subunits/assembly factors).

Conclusions:

• Despite extensive research, a significant number of patients with complex I deficiency lack a molecular diagnosis.
• The discovery of 22 nuclear genes involved suggests many more disease-causing genes for complex I deficiency await identification.