Corydon M J, Andresen B S, Bross P, Kjeldsen M, Andreasen P H, Eiberg H, Kølvraa S, Gregersen N
Research Unit for Molecular Medicine, Faculty of Health Sciences, Aarhus N, Denmark.
Mamm Genome. 1997 Dec;8(12):922-6. doi: 10.1007/s003359900612.
Short-chain acyl-CoA dehydrogenase (SCAD) is a homotetrameric mitochondrial flavoenzyme that catalyzes the initial reaction in short-chain fatty acid beta-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.
短链酰基辅酶A脱氢酶（SCAD）是一种同源四聚体线粒体黄素酶，催化短链脂肪酸β-氧化的初始反应。SCAD酶缺陷与生长发育不良有关，常伴有神经肌肉功能障碍和乙基丙二酸（EMA）尿排泄增加。为了确定患者中SCAD缺乏和乙基丙二酸尿症的遗传基础，我们测定了人类SCAD基因（ACADS）完整编码部分的序列以及所有内含子-外显子边界。SCAD基因长度约为13kb，由10个外显子组成。先前通过对排泄大量EMA的患者成纤维细胞cDNA测序检测到4个多态性位点。其中3个多态性位点（321T/C、990C/T、1260G/C）为沉默变异，而625G/A多态性导致氨基酸替换，并已证明与乙基丙二酸尿症相关。通过对18个不相关的丹麦家庭进行分析，我们发现这4个SCAD基因多态性构成了SCAD基因的5个等位基因变异，并且625A变异与其他3个多态性位点（321C、990T、1260C）较罕见的变异形式共同构成一个等位基因变异，在丹麦普通人群中的频率为22%。使用荧光原位杂交技术，我们证实了人类SCAD基因定位于12号染色体（Chr）的远端，并表明SCAD基因是单拷贝基因。通过两种独立方法研究了SCAD与酰基辅酶A脱氢酶家族其他5个成员之间的进化关系，得到了相似的系统发育树。
