Lack of homozygotes for the most frequent disease allele in carbohydrate-deficient Glycoprotein syndrome type 1A
Lack of homozygotes for the most frequent disease allele in carbohydrate-deficient Glycoprotein syndrome type 1A
复制标题
DOI：
10.1086/301763
复制
发表时间：
1998-03-01
影响因子：
9.8
通讯作者：
Jaeken, J
中科院分区：
文献类型：
--
作者：
Matthijs, G;Schollen, E;Jaeken, J
碳水化合物缺乏糖蛋白综合征1型（CDG 1;也称为“Jaeken综合征”）是一种以糖基化缺陷为特征的常染色体隐性遗传疾病。大多数患者表现出磷酸甘露变位酶（PMM）的缺乏，磷酸甘露变位酶是在GDP-甘露糖合成中将甘露糖6-磷酸转化为甘露糖1-磷酸的酶。该疾病与染色体16 p13有关，最近在PMM缺乏症（CDG 1A）的CDG 1患者中发现了PMM 2基因突变。我们利用PMM 2基因组序列对56例不同地区的CDG 1患者进行了突变筛查。通过SSCP分析和测序，我们发现了23个不同的错义突变和1个单碱基对缺失。总体而言，在CDG 1A患者中99%的疾病染色体上发现了突变。112个疾病等位基因中有43个存在R141 H置换。然而，这种突变从未在纯合状态下观察到，这表明这些改变的纯合与生命不相容。另一方面，发现患者的D 65 Y和F119 L突变为纯合子，因此必须是轻度突变。在比利时和荷兰流行的一种特殊基因型R141 H/D188 G与严重表型和高死亡率相关，除此之外，基因型与临床表型之间的关系有限。
Carbohydrate-deficient-glycoprotein syndrome type 1 (CDG1; also known as "Jaeken syndrome") is an autosomal recessive disorder characterized by defective glycosylation. Most patients show a deficiency of phosphomannomutase (PMM), the enzyme that converts mannose 6-phosphate to mannose 1-phosphate in the synthesis of GDP-mannose. The disease is linked to chromosome 16p13, and mutations have recently seen identified in the PMM2 gene in CDG1 patients with a PMM deficiency (CDG1A). The availability of the genomic sequences of PMM2 allowed us to screen for mutations in 56 CDG1 patients from different geographic origins, By SSCP analysis and by sequencing, we identified 23 different missense mutations and 1 single-base-pair deletion. In total, mutations were found on 99% of the disease chromosomes in CDG1A patients, The R141H substitution is present on 43 of the 112 disease alleles. However, this mutation was never observed in the homozygous state, suggesting that-homozygous for these alterations is incompatible with life. On the other hand, patients were found homozygous for the D65Y and F119L mutations, which must therefore be mild mutations. One particular genotype, R141H/D188G, which is prevalent in Belgium and the Netherlands, is associated with a severe phenotype and a high mortality, Apart from this, there is only a limited relation between the genotype and the clinical phenotype.