IDENTIFICATION OF 4 NEW MUTATIONS IN THE SHORT-CHAIN ACYL-COA DEHYDROGENASE (SCAD) GENE IN 2 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 TOETHYLMALONIC ACIDURIA

Citation
N. Gregersen et al., IDENTIFICATION OF 4 NEW MUTATIONS IN THE SHORT-CHAIN ACYL-COA DEHYDROGENASE (SCAD) GENE IN 2 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 TOETHYLMALONIC ACIDURIA, Human molecular genetics, 7(4), 1998, pp. 619-627
Citations number
39
Language
INGLESE
art.tipo
Article
Categorie Soggetti
Genetics & Heredity",Biology
Journal title
ISSN journal
0964-6906
Volume
7
Issue
4
Year of publication
1998
Pages
619 - 627
Database
ISI
SICI code
0964-6906(1998)7:4<619:IO4NMI>2.0.ZU;2-3
Abstract
We have shown previously that a variant allele of the short-chain acyl -CoA dehydrogenase (SCAD) gene, 625G-->A, is present in homozygous for m in 7% of control individuals and in 60% of 135 patients with elevate d urinary excretion of ethylmalonic acid (EMA). We have now characteri zed three disease-causing mutations (confirmed by lack of enzyme activ ity after expression in COS-7 cells) and a new susceptibility variant in the SCAD gene of two patients with SCAD deficiency, and investigate d their frequency in patients with elevated EMA excretion. The first S CAD-deficient patient was a compound heterozygote for two mutations, 2 74G-->T and 529T-->C. These mutations were not present in 98 normal co ntrol 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 mutatio n was not present in 98 normal alleles, but was detected in three alle les of 133 patients with elevated EMA excretion, consistently as a 625 A-1147T allele. On the other hand, the 511C-->T mutation was present i n 13 of 130 and 15 of 67 625G alleles, respectively, of normal control s and patients with elevated EMA excretion, and was never associated w ith the 625A variant allele, This over-representation of the haplotype 511T-625G among the common 625G alleles in patients compared with con trols was significant (P<0.02), suggesting that the allele 511T-625G-l ike 511C-625A-confers susceptibility to ethylmalonic aciduria, Express ion of the variant. R147W SCAD protein, encoded by the 511T-625G allel e, in COS-7 cells showed 45% activity at 37 degrees C in comparison wi th the wild-type protein, comparable levels of activity at 26 degrees C, and 13% activity when Incubated at 41 degrees C, This temperature p rofile Is different from that observed for the variant G185S SCAD prot ein, encoded by the 511C-625A allele, where higher than normal activit y was found at 26 and 37 degrees C, and 53% activity was present at 41 degrees C, These results corroborate the notion that the 511C-625A va riant allele is one of the possible underlying causes of ethylmalonic aciduria, and suggest that the 511C-->T mutation represents a second s usceptibility variation in the SCAD gene, We conclude that ethylmaloni c aciduria, a commonly detected biochemical phenotype, is a complex mu ltifactorial/polygenic condition where, in addition to the emerging ro le of SCAB susceptibility alleles, other genetic and environmental fac tors are involved.