Identification of four new mutations in the short-chain acyl-CoA dehydrogenase (SCAD) gene in two patients: One of the variant alleles, 511C→T, is present at an unexpectedly high frequency in the general population, as was the case for 625G→A, together conferring susceptibility to ethylmalonic ac... (original) (raw)

We have shown previously that a variant allele of the short-chain acyl-CoA dehydrogenase (SCAD) gene, 625G→A, is present in homozygous form in 7% of control individuals and in 60% of 135 patients with elevated urinary excretion of ethylmalonic acid (EMA). We have now characterized three disease-causing mutations (confirmed by lack of enzyme activity after expression in COS-7 cells) and a new susceptibility variant in the SCAD gene of two patients with SCAD deficiency, and investigated their frequency in patients with elevated EMA excretion. The first SCAD-deficient patient was a compound heterozygote for two mutations, 274G→T and 529T→C. These mutations were not present in 98 normal control alleles, but the 529T→C mutation was found in one allele among 133 patients with elevated EMA excretion. The second patient carried a 1147C→T mutation and the 625G→A polymorphism in one allele, and a single point mutation, 511C→T, in the other. The 1147C→T mutation was not present in 98 normal alleles, but was detected in three alleles of 133 patients with elevated EMA excretion, consistently as a 625A-1147T allele. On the other hand, the 511C→T mutation was present in 13 of 130 and 15 of 67 625G alleles, respectively, of normal controls and patients with elevated EMA excretion, and was never associated with the 625A variant