Extension of the Pompe mutation database by linking disease-associated variants to clinical severity
Extension of the Pompe mutation database by linking disease-associated variants to clinical severity
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DOI：
10.1002/humu.23854
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发表时间：
2019-07-29
期刊：
影响因子：
3.9
通讯作者：
Pijnappel, W. M. Pim
中科院分区：
文献类型：
--
作者：
Nino, Monica Y.;in't Groen, Stijn L. M.;Pijnappel, W. M. Pim
庞贝氏症是一种常染色体隐性溶酶体储积症，由酸性α-葡萄糖苷酶（GAA）基因中的疾病相关变体引起。当前的庞贝氏症突变数据库基于计算机模拟预测和表达研究提供了GAA变体的严重程度评级。在这里，我们用报告的表型的临床信息扩展了数据库。我们增加了对剪接和蛋白质功能的影响以及交叉反应性免疫物质（CRIM）状态、次要等位基因频率和分子分析的额外计算机预测。我们分析了867例患者和562种GAA变异。基于它们与GAA无效等位基因的组合（即，GAA酶活性完全缺乏），422种疾病相关变异中的49%可能与经典的婴儿、儿童或成人表型有关。预测和免疫印迹分析确定了131个CRIM阴性和216个CRIM阳性变体。虽然在整个GAA蛋白中发现了疾病相关的错义变体，但它们在催化位点中富集了7倍。15%的疾病相关错义变异被预测会影响剪接。这应使用剪接测定来证实。在庞贝氏症突变数据库中纳入临床严重程度评级为庞贝氏症的诊断、疾病进展的预后、治疗方案和未来个性化药物的发展提供了宝贵的工具。
Pompe disease is an autosomal recessive lysosomal storage disorder caused by disease-associated variants in the acid alpha-glucosidase (GAA) gene. The current Pompe mutation database provides a severity rating of GAA variants based on in silico predictions and expression studies. Here, we extended the database with clinical information of reported phenotypes. We added additional in silico predictions for effects on splicing and protein function and for cross reactive immunologic material (CRIM) status, minor allele frequencies, and molecular analyses. We analyzed 867 patients and 562 GAA variants. Based on their combination with a GAA null allele (i.e., complete deficiency of GAA enzyme activity), 49% of the 422 disease-associated variants could be linked to classic infantile, childhood, or adult phenotypes. Predictions and immunoblot analyses identified 131 CRIM negative and 216 CRIM positive variants. While disease-associated missense variants were found throughout the GAA protein, they were enriched up to seven-fold in the catalytic site. Fifteen percent of disease-associated missense variants were predicted to affect splicing. This should be confirmed using splicing assays. Inclusion of clinical severity rating in the Pompe mutation database provides an invaluable tool for diagnosis, prognosis of disease progression, treatment regimens, and the future development of personalized medicine for Pompe disease.