High incidence of propionic acidemia in greenland is due to a prevalent mutation, 1540insCCC, in the gene for the beta-subunit of propionyl CoA carboxylase.
High incidence of propionic acidemia in greenland is due to a prevalent mutation, 1540insCCC, in the gene for the beta-subunit of propionyl CoA carboxylase.
复制标题
格陵兰丙酸血症的高发率是由于丙酰辅酶A羧化酶β亚基基因中普遍存在的1540insCCC突变所致。
DOI：
10.1086/302971
复制
发表时间：
2000
影响因子：
9.8
通讯作者：
Schwartz,M
中科院分区：
文献类型：
--
作者：
Ravn,K;Chloupkova,M;Christensen,E;Brandt,NJ;Simonsen,H;Kraus,JP;Nielsen,IM;Skovby,F;Schwartz,M
丙酰辅酶A羧化酶（PCC）是一种线粒体生物素依赖性酶，参与氨基酸、奇数链脂肪酸和其他代谢产物的催化。PCC由α和β两个亚基组成，分别由PCCA和PCCB基因编码。由于任一基因突变导致的遗传性PCC缺陷导致丙酸血症（PA），这是一种常染色体隐性疾病。令人惊讶的是，PA在格陵兰的因纽特人中非常普遍。我们分析了β亚基mRNA的逆转录酶-PCR产物，以表征负责的突变。一个3 bp的插入，1540 insCCC，发现在纯合子形式的3例和复合杂合子形式的1例。所得到的PCC没有可测量的活性，并且突变的β亚基似乎非常不稳定。为了验证一个共同的突变是导致格陵兰因纽特人PA的假设，310个匿名的因纽特人DNA样本进行了1540 insCCC筛查。我们发现携带者的频率为5%，这是非常高的，与大多数其他常染色体隐性遗传病。一个非常紧密连锁的标记D3 S2453的等位基因的分析，揭示了一个特定的等位基因和1540 insCCC之间的高度连锁不平衡，这表明该突变可能是一个创始突变。
Propionyl CoA carboxylase (PCC) is a mitochondrial, biotin-dependent enzyme involved in the catabolism of amino acids, odd-chain fatty acids, and other metabolites. PCC consists of two subunits, α and β, encoded by thePCCAandPCCBgenes, respectively. Inherited PCC deficiency due to mutations in either gene results in propionic acidemia (PA), an autosomal recessive disease. Surprisingly, PA is highly prevalent among Inuits in Greenland. We have analyzed reverse transcriptase–PCR products of the β-subunit mRNA, to characterize the responsible mutation(s). A 3-bp insertion, 1540insCCC, was found in homozygous form in three patients and in compound heterozygous form in one patient. The resulting PCC has no measurable activity, and the mutant β-subunit appears to be very unstable. To test the hypothesis that a common mutation is responsible for PA in the Greenlandic Inuit population, 310 anonymous DNA samples of Inuit origin were screened for 1540insCCC. We found a carrier frequency of 5%, which is very high compared with those of most other autosomal recessive diseases. Analysis of alleles of a very closely linked marker,D3S2453,revealed a high degree of linkage disequilibrium between one specific allele and 1540insCCC, suggesting that this mutation may be a founder mutation.