Human Molecular Genetics, Vol 7, 619-627, Copyright © 1998 by Oxford University Press
N Gregersen, VS Winter, MJ Corydon, TJ Corydon, P Rinaldo, A Ribes, G Martinez, MJ Bennett, C Vianey-Saban, A Bhala, DE Hale, W Lehnert, S Kmoch, M Roig, E Riudor, H Eiberg, BS Andresen, P Bross, LA Bolund and S Kolvraa
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
allele. This over-representation of the haplotype 511T-625G among the
common 625G alleles in patients compared with controls was significant ( P
< 0.02), suggesting that the allele 511T-625G-like 511C-625A- confers
susceptibility to ethylmalonic aciduria. Expression of the variant R147W
SCAD protein, encoded by the 511T-625G allele, in COS-7 cells showed 45%
activity at 37 degrees C in comparison with the wild- type protein,
comparable levels of activity at 26 degrees C, and 13% activity when
incubated at 41 degrees C. This temperature profile is different from that
observed for the variant G185S SCAD protein, encoded by the 511C-625A
allele, where higher than normal activity was found at 26 and 37 degrees C,
and 58% activity was present at 41 degrees C. These results corroborate the
notion that the 511C-625A variant allele is one of the possible underlying
causes of ethylmalonic aciduria, and suggest that the 511C-->T mutation
represents a second susceptibility variation in the SCAD gene. We conclude
that ethylmalonic aciduria, a commonly detected biochemical phenotype, is a
complex multifactorial/polygenic condition where, in addition to the
emerging role of SCAD susceptibility alleles, other genetic and
environmental factors are involved.
ARTICLES
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 aciduria
Research Unit for Molecular Medicine, Faculty of Health Sciences and Aarhus University Hospital, Skejby Sygehus, 8200 Aarhus N, Denmark. NIG@mmf.aau.dk
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