Branched chain acyltransferase absence due to an Alu-based genomic deletion allele and an exon skipping allele in a compound heterozygote proband expressing maple syrup urine disease.
Branched chain acyltransferase absence due to an Alu-based genomic deletion allele and an exon skipping allele in a compound heterozygote proband expressing maple syrup urine disease.
复制标题
表达枫糖浆尿病的复合杂合子先证者中基于 Alu 的基因组缺失等位基因和外显子跳跃等位基因导致支链酰基转移酶缺失。
DOI：
10.1016/0925-4439(92)90043-m
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发表时间：
1992
期刊：
影响因子：
--
通讯作者：
Danner,DJ
中科院分区：
文献类型：
--
作者：
Herring,WJ;McKean,M;Dracopoli,N;Danner,DJ
Branched chain α-ketoacid dehydrogenase assembles around a core of the acyltransferase components on the matrix side of the mitochondrial inner membrane. Autosomal recessive mutations in humans are known to decrease the function of this complex resulting in the clinical phenotype of maple syrup urine disease. Within this wide group of mutations are a subset which result in the antigenic absence of the acyltransferase protein of the complex. Here we describe two mutations in a compound heterozygote proband which result in this acyltransferase-negative phenotype. The mutant allele inherited from the father lacks 15–20 kilobases of genomic DNA resulting from a recombinational event between an intronic Alu sequence and coding sequence in the terminal exon. The mother's mutant allele contains a single base substitution in the −1 position of the 5′ splice junction following exon 8. This G1002→ A transition results in exon skipping producing two different mRNAs. The first lacks only exon 8 while the second lacks exons 8–10. All mRNAs for the acyltransferase found in cells from the proband have the potential to produce proteins ranging in size from 251–395 amino acids, the largest being 26 amino acid short of a full-length acyltransferase. The potential of these transcripts to produce protein is of interest since the patient is clinically responsive to pharmacologic treatment with thiamin, showing a higher tolerance to protein in the diet. The mechanism for this thiamin response remains to be explained.
