Sequence variations in the NDUFA1 gene encoding a subunit of complex I of the respiratory chain

NDUFA1 is one of the 36 nuclear genes encoding subunits of the mitochondria l complex I involved in the respiratory chain. The human NDUFA1 has been cl oned, completely sequenced and mapped to Xq24. In the present study, we sea rched for sequence variations in NDUFA1 as causative defects in complex I d eficiency using genomic DNA of 152 patients with various clinical phenotype s. The patient sample consisted of 54 patients (46 male and 8 female) with Leber heriditary optic neuropathy (LHON) from 48 unrelated families from Ge rmany and 98 patients (72 male and 26 female) with biochemically proven com plex I deficiency including Leigh syndrome. Patient DNA was used to amplify all three exons, including the exon/intron boundaries and the promoter reg ion of NDUFA1 for heteroduplex analysis and direct sequencing. In the 152 p atients tested, no mutation was found that could be related to any of the d isease phenotypes included. However, three single-nucleotide polymorphisms (SNPs) located in the promoter region (SNP G/C at nt -71 and SNP T/C at nt -189) and in intron 1 (SNP T/G nt 1454) were discovered. Allele frequencies of the SNPs were estimated in a German and Estonian control population and compared to complex I-deficient patients. There was no significant differe nce between the control population, the LHON patients, or the severely affe cted patients with complex I deficiency, excluding an association of the po lymorphisms with the diseases. Our results suggest that mutations in NDUFA1 do not cause the gender difference observed in clinically severe and compl ex phenotypes with complex I deficiency.