Zhang Z, Kolvraa S, Zhou Y, Kelly D P, Gregersen N, Strauss A W
Department of Pediatrics, Washington University School of Medicine, St Louis, MO.
Am J Hum Genet. 1993 Jun;52(6):1111-21.
Medium-chain acyl-CoA dehydrogenase (MCAD) deficiency is a common inborn error of fatty-acid oxidation and may cause sudden infant death. Previous studies revealed that (i) homozygosity for an A-to-G mutation at nucleotide 985 of the mRNA coding region (A985G) is an extremely common cause of MCAD deficiency and (ii) MCAD deficiency is strongly associated with a particular haplotype for RFLPs for BanII, PstI, and TaqI. TaqI allele 2 is always associated with the A985G mutation in human MCAD deficiency. In this study, we have delineated the molecular basis of the RFLPs for PstI, BamHI, and TaqI in the human MCAD gene. Our results prove that the three RFLPs are caused by point mutations in the 8 kb of DNA encompassing exons 8-10 of the human MCAD gene. The TaqI polymorphism is caused by a C-to-A substitution 392 bp upstream of the exon 8, and the PstI and BamHI polymorphisms are due to T-to-C and G-to-A substitutions, respectively, which are 727 and 931 bp downstream of exon 10 respectively. All three RFLPs lie within Alu repetitive sequences. Comparison of intronic sequences immediately following exon 10 from two normal individuals with different haplotypes showed that this region contains densely packed Alu repeats and is highly polymorphic. Our results are consistent both with a founder effect as the cause of the high prevalence of a single (A985G) mutation in MCAD deficiency and with its association with a particular haplotype for these intragenic RFLPs.
中链酰基辅酶A脱氢酶（MCAD）缺乏症是一种常见的脂肪酸氧化先天性代谢缺陷病，可能导致婴儿猝死。既往研究表明：（i）mRNA编码区第985位核苷酸由A突变为G（A985G）的纯合子是MCAD缺乏症极为常见的病因；（ii）MCAD缺乏症与BanII、PstI和TaqI限制性片段长度多态性（RFLP）的特定单倍型密切相关。在人类MCAD缺乏症中，TaqI等位基因2总是与A985G突变相关。在本研究中，我们阐明了人类MCAD基因中PstI、BamHI和TaqI的RFLP分子基础。我们的结果证明，这三种RFLP是由人类MCAD基因外显子8至10的8kb DNA中的点突变引起的。TaqI多态性是由外显子8上游392bp处的C到A替换引起的，PstI和BamHI多态性分别是由外显子10下游727bp和931bp处的T到C和G到A替换引起的。所有三种RFLP都位于Alu重复序列内。比较两个具有不同单倍型的正常个体外显子10之后的内含子序列，发现该区域含有密集排列的Alu重复序列，且高度多态。我们的结果既与单一（A985G）突变在MCAD缺乏症中高患病率的奠基者效应一致，也与该突变与这些基因内RFLP的特定单倍型的关联一致。
