NDUFS2 – Mitochondrial Complex I Deficiency

Mitochondrial complex I deficiency is the most frequent oxidative phosphorylation disorder in infants and children and presents with a spectrum ranging from Leigh syndrome to progressive leukoencephalopathy. NDUFS2 encodes the 49-kDa subunit of complex I and follows an autosomal recessive inheritance pattern. Initial screening in consanguineous families identified three missense substitutions in conserved residues (p.Arg228Gln, p.Pro229Gln, p.Ser413Pro) across three independent pedigrees (PMID:11220739). Subsequent cohort sequencing in 34 affected children revealed four additional probands harboring compound heterozygous NDUFS2 variants, including a recurrent c.875T>C (p.Met292Thr) allele shared by three families via an ancient founder event and a novel splice-site variant c.866+4A>G (PMID:20819849).

A separate report described a homozygous c.1336G>A (p.Asp446Asn) change in a patient with Leigh syndrome and hypertrophic cardiomyopathy, in whom complex I activity was profoundly reduced despite normal assembly; wild-type NDUFS2 transduction fully rescued enzymatic function (PMID:22036843). Together, these studies account for at least eight unrelated probands with biallelic missense or splice variants in NDUFS2. The variant spectrum comprises five missense and one splice variant, with a demonstrated founder M292T allele in Caucasian families.

Functional assays confirm a loss-of-function mechanism. In patient fibroblasts carrying the Asp446Asn mutation, complex I activity is severely impaired but restored by wild-type gene complementation. Cryo-EM and EPR analyses of engineered R121M/K mutants further show destabilization and loss of the N2 FeS cluster, abrogating quinone-reductase activity (PMID:33640456). These concordant biochemical and structural data underscore the critical role of NDUFS2 in complex I catalysis.

No conflicting reports have been described for NDUFS2, and the gene–disease association has been replicated in multiple laboratories over more than a decade. Segregation in recessive consanguineous pedigrees and the rescue of function in patient cells provide robust experimental support. This collective evidence fulfills ClinGen criteria for a Definitive gene–disease relationship.

Key Take-home: Biallelic NDUFS2 variants cause autosomal recessive mitochondrial complex I deficiency, and genetic testing of this gene should be part of the diagnostic workup for children presenting with Leigh syndrome or progressive leukoencephalopathy.

References

• Annals of neurology • 2001 • Mutations in the complex I NDUFS2 gene of patients with cardiomyopathy and encephalomyopathy. PMID:11220739
• Brain : a journal of neurology • 2010 • The p.M292T NDUFS2 mutation causes complex I-deficient Leigh syndrome in multiple families. PMID:20819849
• Biochimica et biophysica acta • 2012 • A catalytic defect in mitochondrial respiratory chain complex I due to a mutation in NDUFS2 in a patient with Leigh syndrome. PMID:22036843
• The Journal of biological chemistry • 2021 • A conserved arginine residue is critical for stabilizing the N2 FeS cluster in mitochondrial complex I. PMID:33640456

Evidence Based Scoring (AI generated)