The demographics and distribution of type B Niemann-Pick disease: Novel mutations lead to new genotype/phenotype correlations
The demographics and distribution of type B Niemann-Pick disease: Novel mutations lead to new genotype/phenotype correlations
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DOI：
10.1086/345074
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发表时间：
2002-12-01
影响因子：
9.8
通讯作者：
Schuchman, EH
中科院分区：
文献类型：
--
作者：
Simonaro, CM;Desnick, RJ;Schuchman, EH
我们收集了全球 394 名 B 型尼曼-匹克病 (NPD) 患者样本的人口统计和/或突变信息。这种疾病是泛种族的，土耳其、阿拉伯和北非血统的人发病率最高。 394 名患者中只有 5 名是德系犹太人，这表明与 A 型 NPD 不同，B 型 NPD 在该人群中并不常见。对 228 名患者（324 个独特的等位基因）进行酸性鞘磷脂酶 (ASM) 基因（称为“SMPD1”）的突变分析，发现了几种新的“常见”突变。其中，L137P、fsP189和L549P突变，占土耳其患者等位基因的75%，H421Y和K576N突变，占沙特阿拉伯患者等位基因的85%，S379P、R441X、R474W和F480L突变，占沙特阿拉伯患者等位基因的55%。葡萄牙/巴西患者，A196P突变，占苏格兰/英国患者等位基因的42%。之前报道的 DeltaR608 突变发生在大约 12% 的研究等位基因上。总体而言，总共发现了 45 个新突变，并确定了一些新的基因型/表型相关性。特别是，L137P、A196P 和 R474W 突变与 B 型 NPD 的较轻形式一致，而 H421Y 和 K576N 突变导致沙特阿拉伯特有的早发、更严重形式。这些数据首次对这种疾病进行了广泛的人口统计评估，并描述了几种新的突变，可用于预测表型结果并获得对 ASM 结构和功能的新见解。
We have collected demographic and/or mutation information on a worldwide sample of 394 patients with type B Niemann-Pick disease (NPD). The disorder is panethnic, with the highest incidence occurring in individuals of Turkish, Arabic, and North African descent. Only five of the 394 patients were Ashkenazi Jewish, revealing that, unlike the type A form of NPD, type B NPD does not occur frequently within this population. Mutation analysis of the acid sphingomyelinase (ASM) gene (designated "SMPD1") was performed on 228 patients (324 unique alleles), and several novel, "common" mutations were found. Among these were the L137P, fsP189, and L549P mutations, which accounted for similar to75% of the alleles in Turkish patients, the H421Y and K576N mutations, which accounted for similar to85% of the alleles in Saudi Arabian patients, the S379P, R441X, R474W, and F480L mutations, which accounted for similar to55% of the alleles in Portuguese/Brazilian patients, and the A196P mutation, which accounted for similar to42% of the alleles in Scottish/English patients. The previously reported DeltaR608 mutation occurred on similar to12% of the alleles studied. Overall, a total of 45 novel mutations were found, and several new genotype/phenotype correlations were identified. In particular, the L137P, A196P, and R474W mutations were consistent with a less severe form of type B NPD, whereas the H421Y and K576N mutations led to an early-onset, more severe form that was specific to Saudi Arabia. These data provide the first extensive demographic assessment of this disorder and describe several new mutations that can be used to predict phenotypic outcome and to gain new insights into the structure and function of ASM.