A polymorphic variant in the human electron transfer flavoprotein alpha-chain (alpha-T171) displays decreased thermal stability and is overrepresented in very-long-chain acyl-CoA dehydrogenase-deficient patients with mild childhood presentation.

The consequences of two amino acid polymorphisms of human electron transfer flavoprotein (alpha-T/I171 in the alpha-subunit and beta-M/T154 in the beta-subunit) on the thermal stability of the enzyme are described. The alpha-T171 variant displayed a significantly decreased thermal stability, whereas the two variants of the beta-M/T154 polymorphism did not differ. We wished to test the hypothesis that these polymorphisms might constitute susceptibility factors and therefore determined their allele and genotype frequencies in (i) control individuals, (ii) medium-chain acyl-CoA dehydrogenase-deficient patients homozygous for the K304E mutation (MCAD E304), (iii) a group of patients with elevated urinary excretion of ethylmalonic acid (EMA) possibly due to decreased short-chain acyl-CoA dehydrogenase activity, and (iv) in patients with proven deficiency of very-long-chain acyl-CoA dehydrogenase (VLCAD). No significant overrepresentations or underrepresentations were found in the first two patient groups, suggesting that the polymorphisms studied are not significant susceptibility factors in either the MCAD E304 or the EMA patient group. However, in the VLCAD deficient patients the alpha-T171 variant (decreased thermal stability) was significantly overrepresented. Subgrouping of the VLCAD patients into three phenotypic classes (severe childhood, mild childhood, and adult presentation) revealed that the overrepresentation of the alpha-T171 variant was significant only in patients with mild childhood presentation. This is compatible with a negative modulating effect of the less-stable alpha-T171 ETF variant in this group of VLCAD patients that harbor missense mutations in at least one allele and therefore potentially display residual levels of VLCAD enzyme activity.