AN UNUSUAL INSERTION DELETION IN THE GENE ENCODING THE BETA-SUBUNIT OF PROPIONYL-COA CARBOXYLASE IS A FREQUENT MUTATION IN CAUCASIAN PROPIONIC ACIDEMIA
AN UNUSUAL INSERTION DELETION IN THE GENE ENCODING THE BETA-SUBUNIT OF PROPIONYL-COA CARBOXYLASE IS A FREQUENT MUTATION IN CAUCASIAN PROPIONIC ACIDEMIA
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DOI：
10.1073/pnas.87.4.1372
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发表时间：
1990-02-01
影响因子：
11.1
通讯作者：
ROSENBERG, LE
中科院分区：
文献类型：
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作者：
TAHARA, T;KRAUS, JP;ROSENBERG, LE
丙酸血症是由丙酰辅酶A羧化酶（PCC; EC 6.4.1.3）缺乏引起的有机酸代谢的遗传性病症。受影响的患者分为两个互补组，pccA和pccBC（亚组B、C和BC），这是由于不相同的α缺陷引起的。和βPCC的亚基。我们已经在来自pccBC和pccC亚组的患者的DNA中检测到一种不寻常的插入/缺失，其替换了β的编码序列中的14个核苷酸。与该基因区域无关的12个核苷酸的亚基。这导致在新的框架中消除N Msp I限制性位点、2个碱基对（bp）缺失、移码和终止密码子。靠近正常羧基末端的100个氨基酸残基。在pccBC互补组的14名无关的白人患者中，在检查的28个突变等位基因中的8个中发现了这种独特的突变。突变体等位基因特异性寡核苷酸与扩增的基因组DNA的杂交显示，插入的12个核苷酸不起源于等位基因。突变周围1000 bp的区域。在我们的研究过程中，我们确定了同一外显子中的另一个突变：一个3 bp的框内缺失，消除了两个异亮氨酸密码子之一，紧接在Msp I位点之前。两个不相关的患者是这种单密码子缺失和上述插入/缺失的复合杂合子。我们得出结论，或者存在PCC β-亚基基因在这个位置发生这种突变，或者更有可能的是，所有涉及的高加索患者的突变在前几代都有共同的起源。
Propionic acidemia is an inherited disorder of organic acid metabolism that is caused by deficiency of propionyl-CoA carboxylase (PCC; EC 6.4.1.3). Affected patients fall into two complementation groups, pccA and pccBC (subgroups B, C, and BC), resulting from deficiency of the nonidentical .alpha. and .beta. subunits of PCC, respectively. We have detected an unusual insertion/deletion in the DNA of patients from the pccBC and pccC subgroups that replaces 14 nucleotides in the coding sequence of the .beta. subunit with 12 nucleotides unrelated to this region of the gene. This results in elmination of N Msp I restriction site, a 2-base-pair (bp) deletion, a frameshift, and a stop codon in the new frame .apprxeq. 100 amino acid residues proximal to the normal carboxyl terminus. Among 14 unrelated Caucasian patients in the pccBC complementation group, this unique mutation was found in 8 of 28 mutant alleles examined. Mutant allele-specific oligonucleotide hybridization to amplified genomic DNAs revealed that the inserted 12 nucleotides do not originate in an .apprxeq. 1000-bp region around the mutation. In the course of our investigation, we identified another mutation in the same exon: a 3-bp in-frame deletion that eliminates one of two isoleucine codons immediately preceding the Msp I site. Two unrelated patients were compound heterozygotes for this single-codon deletion and for the insertion/deletion described above. We conclude that either there is a propensity for the PCC .beta.-subunit gene to undergo mutations of this sort at this position or, more likely, the mutations in all of the involved Caucasian patients have a common origin in preceding generations.