Stone D L, Tayebi N, Orvisky E, Stubblefield B, Madike V, Sidransky E
Clinical Neuroscience Branch, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland 20892-4405, USA.
Hum Mutat. 2000;15(2):181-8. doi: 10.1002/(SICI)1098-1004(200002)15:2<181::AID-HUMU7>3.0.CO;2-S.
Gaucher disease, the most common lysosomal storage disorder, results from the inherited deficiency of the enzyme glucocerebrosidase. Three clinical types are recognized: type 1, non-neuronopathic; type 2, acute neuronopathic; and type 3, subacute neuronopathic. Type 2 Gaucher disease, the rarest type, is progressive and fatal. We have performed molecular analyses of a cohort of 31 patients with type 2 Gaucher disease. The cases studied included fetuses presenting prenatally with hydrops fetalis, infants with the collodion baby phenotype, and infants diagnosed after several months of life. All 62 mutant glucocerebrosidase (GBA) alleles were identified. Thirty-three different mutant alleles were found, including point mutations, splice junction mutations, deletions, fusion alleles and recombinant alleles. Eleven novel mutations were identified in these patients: R131L, H255Q, R285H, S196P, H311R, c.330delA, V398F, F259L, c.533delC, Y304C and A190E. Mutation L444P was found on 25 patient alleles. Southern blots and direct sequencing demonstrated that mutation L444P occurred alone on 9 alleles, with E326K on one allele and as part of a recombinant allele on 15 alleles. There were no homozygotes for point mutation L444P. The recombinant alleles that included L444P resulted from either reciprocal recombination or gene conversion with the nearby glucocerebrosidase pseudogene, and seven different sites of recombination were identified. Homozygosity for a recombinant allele was associated with early lethality. We have also summarized the literature describing mutations associated with type 2 disease, and list 50 different mutations. This report constitutes the most comprehensive molecular study to date of type 2 Gaucher disease, and it demonstrates that there is significant phenotypic and genotypic heterogeneity among patients with type 2 Gaucher disease. Hum Mutat 15:181-188, 2000. Published 2000 Wiley-Liss, Inc.
戈谢病是最常见的溶酶体贮积症，由葡萄糖脑苷脂酶的遗传性缺乏引起。已确认有三种临床类型：1型，非神经病变型；2型，急性神经病变型；3型，亚急性神经病变型。2型戈谢病最为罕见，呈进行性且致命。我们对31例2型戈谢病患者进行了分子分析。所研究的病例包括产前出现胎儿水肿的胎儿、具有火棉胶婴儿表型的婴儿以及出生数月后确诊的婴儿。共鉴定出62个突变的葡萄糖脑苷脂酶（GBA）等位基因。发现了33种不同的突变等位基因，包括点突变、剪接连接突变、缺失、融合等位基因和重组等位基因。在这些患者中鉴定出11种新突变：R131L、H255Q、R285H、S196P、H311R、c.330delA、V398F、F259L、c.533delC、Y304C和A190E。在25个患者等位基因上发现了L444P突变。Southern印迹和直接测序表明，L444P突变单独出现在9个等位基因上，在1个等位基因上与E326K同时出现，在另外15个等位基因上作为重组等位基因的一部分出现。不存在L444P点突变的纯合子。包含L444P的重组等位基因是由与附近葡萄糖脑苷脂酶假基因的相互重组或基因转换产生的，并且鉴定出了7个不同的重组位点。重组等位基因的纯合性与早期致死性相关。我们还总结了描述与2型疾病相关突变的文献，并列出了50种不同的突变。本报告是迄今为止对2型戈谢病最全面的分子研究，它表明2型戈谢病患者之间存在显著的表型和基因型异质性。《人类突变》15:181 - 188，2000年。2000年由Wiley - Liss公司出版。
