Pittis M G, Donnarumma M, Montalvo A L E, Dominissini S, Kroos M, Rosano C, Stroppiano M, Bianco M G, Donati M A, Parenti G, D'Amico A, Ciana G, Di Rocco M, Reuser A, Bembi B, Filocamo M
Unità di Malattie Metaboliche, IRCCS Burlo Garofolo, Trieste, Italy.
Hum Mutat. 2008 Jun;29(6):E27-36. doi: 10.1002/humu.20753.
We characterized 29 unrelated patients presenting with the severe form of Pompe disease (Glycogen Storage Disease Type II, acid maltase deficiency) and identified 26 pathogenic mutations divided over 28 different genotypes. Among the eight new mutations, five were exonic point mutations (c.572A>G, c.1124G>T, c.1202A>G, c.1564C>G and c.1796C>A) leading to codon changes (p.Y191C, p.R375L, p.Q401R, p.P522A and p.S599Y); two were intronic point mutations (c.-32-3C>A and c.1636+5G>C) affecting mRNA processing; one was a single base deletion (c.742delC) generating a truncated protein (p.L248PfsX20). A comprehensive evaluation, based on different methodological approaches, confirmed the detrimental effect of the eight mutations on the protein and its function. Structural alterations potentially induced by the five missense mutations were also predicted through visual inspection of the atomic model of the GAA protein, in terms of both function and spatial orientation of specific residues as well as disturbance generated by amino acid substitutions. Although the remarkable heterogeneity of the mutational spectrum in Pompe disease was already known, our data demonstrate and confirm the power of molecular and functional analysis in predicting the natural course of Pompe disease.
我们对29例患有严重形式的庞贝病（糖原贮积病II型，酸性麦芽糖酶缺乏症）的非亲缘关系患者进行了特征分析，鉴定出26种致病突变，分布在28种不同的基因型中。在这8种新突变中，5种是外显子点突变（c.572A>G、c.1124G>T、c.1202A>G、c.1564C>G和c.1796C>A），导致密码子改变（p.Y191C、p.R375L、p.Q401R、p.P522A和p.S599Y）；2种是内含子点突变（c.-32-3C>A和c.1636+5G>C），影响mRNA加工；1种是单碱基缺失（c.742delC），产生截短蛋白（p.L248PfsX20）。基于不同方法学途径的综合评估证实了这8种突变对蛋白质及其功能的有害影响。还通过直观检查GAA蛋白的原子模型，从特定残基的功能和空间取向以及氨基酸取代产生的干扰方面，预测了5种错义突变可能诱导的结构改变。尽管庞贝病突变谱的显著异质性已为人所知，但我们的数据证明并确认了分子和功能分析在预测庞贝病自然病程方面的作用。
