Structural organization of the human short-chain acyl-CoA dehydrogenase gene |
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Authors: | Morten Juhl Corydon Brage Storstein Andresen Peter Bross Margrethe Kjeldsen Per Hove Andreasen Hans Eiberg Steen Kølvraa Nils Gregersen |
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Institution: | (1) Research Unit for Molecular Medicine, Faculty of Health Sciences and Aarhus University Hospital SKS, Skejby Sygehus, DK-8200 Aarhus N, Denmark, DK;(2) Danish Center for Human Genome Research, Aarhus University, DK-8000 Aarhus C, Denmark, DK;(3) Institute of Medical Genetics, Panum Institute, University of Copenhagen, DK-2200 Copenhagen N, Denmark, DK;(4) Department of Clinical Genetics, Aarhus University Hospital, Bartholin Building, DK-8000 Aarhus C, Denmark, DK |
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Abstract: | Short-chain acyl-CoA dehydrogenase (SCAD) is a homotetrameric mitochondrial flavoenzyme that catalyzes the initial reaction
in short-chain fatty acid β-oxidation. Defects in the SCAD enzyme are associated with failure to thrive, often with neuromuscular
dysfunction and elevated urinary excretion of ethylmalonic acid (EMA). To define the genetic basis of SCAD deficiency and
ethylmalonic aciduria in patients, we have determined the sequence of the complete coding portion of the human SCAD gene (ACADS)
and all of the intron-exon boundaries. The SCAD gene is approximately 13 kb in length and consists of 10 exons. Four polymorphic
sites have previously been detected by sequencing of cDNA from fibroblasts of patients excreting elevated amounts of EMA.
Three of these polymorphisms (321T/C, 990C/T, 1260G/C) are silent variants, while a 625G/A polymorphism results in an amino
acid replacement and has been shown to be associated with ethylmalonic aciduria. From analysis of 18 unrelated Danish families,
we show that the four SCAD gene polymorphisms constitute five allelic variants of the SCAD gene, and that the 625A variant
together with the less frequent variant form of the three other polymorphisms (321C, 990T, 1260C) constitutes an allelic variant
with a frequency of 22% in the general Danish population. Using fluorescence in-situ hybridization, we confirm the localization
of the human SCAD gene to the distal part of Chromosome (Chr) 12 and suggest that the SCAD gene is a single-copy gene. The
evolutionary relationship between SCAD and five other members of the acyl-CoA dehydrogenase family was investigated by two
independent approaches that gave similar phylogenetic trees.
Received: 10 April 1997 / Accepted: 8 August 1997 |
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