NDUFA1 – Mitochondrial Complex I Deficiency

NDUFA1 encodes the mitochondrial MWFE subunit of respiratory chain complex I, essential for electron transport and ATP production. The gene is X-linked and hemizygous variants manifest predominantly in males with complex I deficiency and Leigh syndrome (PMID:11286378).

Initial pathogenic variants were identified in two unrelated male patients with Leigh syndrome and myoclonic epilepsy/developmental delay: c.22G>C (p.Gly8Arg) and c.111G>C (p.Arg37Ser) (PMID:17262856). A third hemizygous missense variant, c.55C>T (p.Pro19Ser), was reported in a Leigh syndrome patient after mtDNA exclusion and cybrid studies (PMID:25356405).

Inheritance is X-linked recessive, with affected males harboring hemizygous variants absent in control populations. No large pedigrees have been described, but variant segregation in males supports pathogenicity (PMID:17262856).

Functional assays demonstrate that patient fibroblasts with p.Gly8Arg and p.Arg37Ser show decreased intact complex I levels and compromised assembly/stability (PMID:17262856). Site-directed mutagenesis of NDUFA1 in a null hamster cell line yields reduced complex I activity (PMID:11695834). An Ndufa1S55A knock-in mouse model exhibits ~50% residual complex I activity, neurodegeneration, and Purkinje cell loss, mirroring human disease (PMID:28506826).

A screening of 152 patients with confirmed complex I deficiency, including Leigh syndrome and LHON, detected only benign promoter and intronic SNPs in NDUFA1, indicating that disease-causing variants are rare but specific to individual families (PMID:11286378).

Integration of genetic and experimental data supports a model of NDUFA1 loss-of-function causing complex I assembly defects and Leigh syndrome in hemizygous males. Additional nuclear and mtDNA genes contribute to complex I deficiency heterogeneity. Routine inclusion of NDUFA1 in diagnostic sequencing panels is recommended for male patients with suspected complex I deficiency.

Key Take-home: Screening for X-linked NDUFA1 variants enhances molecular diagnosis of complex I deficiency in affected males.

References

• Journal of inherited metabolic disease • 2001 • Sequence variations in the NDUFA1 gene encoding a subunit of complex I of the respiratory chain PMID:11286378
• Annals of neurology • 2007 • X-linked NDUFA1 gene mutations associated with mitochondrial encephalomyopathy PMID:17262856
• Annals of clinical and translational neurology • 2014 • New MT-ND6 and NDUFA1 mutations in mitochondrial respiratory chain disorders PMID:25356405
• Journal of bioenergetics and biomembranes • 2001 • Molecular genetics of the mammalian NADH-ubiquinone oxidoreductase PMID:11695834
• Neurochemistry international • 2017 • An X-chromosome linked mouse model (Ndufa1S55A) for systemic partial Complex I deficiency for studying predisposition to neurodegeneration and other diseases PMID:28506826

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