GENETIC-HETEROGENEITY IN TYPE-1 GAUCHER DISEASE - MULTIPLE GENOTYPES IN ASHKENAZIC AND NON-ASHKENAZIC INDIVIDUALS
GENETIC-HETEROGENEITY IN TYPE-1 GAUCHER DISEASE - MULTIPLE GENOTYPES IN ASHKENAZIC AND NON-ASHKENAZIC INDIVIDUALS
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DOI：
10.1073/pnas.85.7.2349
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发表时间：
1988-04-01
影响因子：
11.1
通讯作者：
GINNS, EI
中科院分区：
文献类型：
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作者：
TSUJI, S;MARTIN, BM;GINNS, EI
对德系犹太1型戈谢病患者基因组克隆的核苷酸序列分析显示，葡萄糖脑苷酶基因第9外显子存在单碱基突变（腺苷向鸟苷过渡）。这种变化导致丝氨酸取代天冬酰胺。对正常cDNA进行寡核苷酸定向诱变后的瞬时表达研究证实，突变导致葡萄糖脑苷酶活性的丧失。等位基因特异性杂交与寡核苷酸探针表明，该突变仅存在于1型表型。6例2型患者、11例3型患者和12例正常对照均无该等位基因。相比之下，24例1型患者中有15例具有该突变的等位基因，另外3例为该突变的纯合等位基因。此外，一些德系犹太人1型患者只有一个等位基因具有这种突变，这表明即使在这个人群中也存在等位基因杂合性。这些发现表明，在犹太人和非犹太人人群中都存在导致1型戈谢病的多个等位基因突变。等位基因特异性杂交显示外显子9突变，与Nci限制性片段长度多态性（被描述为神经性戈谢病的标记）结合使用，为诊断和遗传咨询提供了一种工具。在所有戈歇患者中80%的信息。
Nucleotide sequence analysis of a genomic clone from an Ashkenazic Jewish patient with type 1 Gaucher disease revealed a sigle-base mutation (adenosine to guanosine transition) in exon 9 of the glucocerebrosidase gene. This change results in the amino acid substitution of serine for asparagine. Transient expression studies following oligonucleotide-directed mutagenesis of the normal cDNA confirmed that the mutation results in loss of glucocerebrosidase activity. Allele-specific hybridization with oligonucleotide probes demonstrated that this mutation was found exclusively in the type 1 phenotype. None of the 6 type 2 patients, 11 type 3 patients, or 12 normal controls had this allele. In contrast, 15 of 24 type 1 patients had one allele with this mutation, and 3 others were homozygous for the mutation. Furthermore, some of the Ashkenazic Jewish type 1 patients had only one allele with this mutation, suggesting that even in this population there is allelic heterozygosity. These findings indicate that there are multiple allelic mutations responsible for type 1 Gaucher disease in both the Jewish and non-Jewish populations. Allelic-specific hybridization demonstrating this mutation in exon 9, used in conjunction with the Nci I restriction fragment length polymorphism described as a marker for neuronopathic Gaucher disease, provides a tool for diagnosis and genetic counseling that is .apprxeq. 80% informative in all Gaucher patients studied.