Analysis and classification of 304 mutant alleles in patients with type 1 and type 3 Gaucher disease
Analysis and classification of 304 mutant alleles in patients with type 1 and type 3 Gaucher disease
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DOI：
10.1086/302925
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发表时间：
2000-06-01
影响因子：
9.8
通讯作者：
Sidransky, E
中科院分区：
文献类型：
--
作者：
Koprivica, V;Stone, DL;Sidransky, E
戈谢病是由葡萄糖脑苷脂酶的遗传性缺乏引起的（EC 3.2.1.45）。尽管已经描述了人葡萄糖脑苷脂酶基因中>100个突变，但大多数基因型-表型研究集中在筛选少数常见突变上。在这项研究中，我们使用了几种方法，包括直接测序，Southern印迹，长模板PCR，限制性内切酶，和扩增折射突变系统（ARMS）的基因型128例患者1型戈谢病（64德系犹太血统和64非犹太血统）和24例患者3型戈谢病。超过97%的突变等位基因被鉴定。检测到14个新突变（A90 T、N117 D、T134 I、Y135 X、R170 C、W184 R、A190 T、Y304 X、A341 T、D399 Y、c.153- 154 insTACAGC、c.203- 204 insC、c.222- 224 delTAC和c.1122- 1123 insTG）和许多罕见突变。重组等位基因在19%的患者中被发现。尽管我们的德系犹太人1型患者中93%的突变等位基因是N370 S、c.84- 85 insG、IVS 2 +1G-->A或L444 P，但这四种突变仅占非犹太人1型患者中突变等位基因的49%。基因型-表型相关性进行了尝试，纯合性或杂合性N370 S导致1型戈谢病，而纯合性L444 P与3型。基因型L444 P/重组等位基因导致2型戈谢病，重组等位基因的纯合性与围产期致死性疾病相关。其他突变的表型结果，特别是R463 C，更不一致。我们的研究结果表明，突变检测率高，大量的新的和罕见的突变，和重组等位基因的患病率的准确评估，虽然一些基因型-表型相关性确实存在，其他遗传和环境因素也必须有助于遇到的表型，我们警告不要仅仅依靠基因型的预后或治疗判断。
Gaucher disease results from the inherited deficiency of the enzyme glucocerebrosidase (EC 3.2.1.45). Although >100 mutations in the gene for human glucocerebrosidase have been described, most genotype-phenotype studies have focused upon screening for a few common mutations. In this study, we used several approaches-including direct sequencing, Southern blotting, long-template PCR, restriction digestions, and the amplification refraction mutation system (ARMS)-to genotype 128 patients with type 1 Gaucher disease (64 of Ashkenazi Jewish ancestry and 64 of non-Jewish extraction) and 24 patients with type 3 Gaucher disease. More than 97% of the mutant alleles were identified. Fourteen novel mutations (A90T, N117D, T134I, Y135X, R170C, W184R, A190T, Y304X, A341T, D399Y, c.153-154insTACAGC, c.203-204insC, c.222-224delTAC, and c.1122-1123insTG) and many rare mutations were detected. Recombinant alleles were found in 19% of the patients. Although 93% of the mutant alleles in our Ashkenazi Jewish type 1 patients were N370S, c.84-85insG, IVS2+1G-->A or L444P, these four mutations accounted for only 49% of mutant alleles in the non-Jewish type 1 patients. Genotype-phenotype correlations were attempted, Homozygosity or heterozygosity for N370S resulted in type 1 Gaucher disease, whereas homozygosity for L444P was associated with type 3. Genotype L444P/recombinant allele resulted in type 2 Gaucher disease, and homozygosity for a recombinant allele was associated with perinatal lethal disease. The phenotypic consequences of other mutations, particularly R463C, were more inconsistent. Our results demonstrate a high rate of mutation detection, a large number of novel and rare mutations, and an accurate assessment of the prevalence of recombinant alleles, Although some genotype-phenotype correlations do exist, other genetic and environmental factors must also contribute to the phenotypes encountered, and we caution against relying solely upon genotype for prognostic or therapeutic judgements.