Update of the pompe disease mutation database with 60 novel GAA sequence variants and additional studies on the functional effect of 34 previously reported variants

被引:58
作者
Kroos, Marian [1 ,2 ]
Hoogeveen-Westerveld, Marianne [1 ,2 ]
Michelakakis, Helen [3 ]
Pomponio, Robert [4 ]
Van der Ploeg, Ans [1 ,2 ]
Halley, Dicky [1 ,2 ]
Reuser, Arnold [1 ,2 ]
机构
[1] Erasmus MC, Dept Clin Genet, Ctr Lysosomal & Metab Dis, Rotterdam, Netherlands
[2] Erasmus MC, Dept Paediat, Ctr Lysosomal & Metab Dis, Rotterdam, Netherlands
[3] Inst Child Hlth, Dept Enzymol & Cellular Funct, Athens, Greece
[4] Genzyme Corp, Clin Lab Sci Grp, Framingham, MA 01701 USA
关键词
GAA; Pompe disease; alpha-glucosidase; acid maltase; glycogenosis; lysosomal storage disorder;
D O I
10.1002/humu.22108
中图分类号
Q3 [遗传学];
学科分类号
071007 ; 090102 ;
摘要
Pompe disease is an autosomal recessive lysosomal glycogen storage disorder, characterized by progressive muscle weakness. Deficiency of acid a-glucosidase (EC; 3.2.1.20/3) can be caused by numerous pathogenic variants in the GAA gene. The Pompe Disease Mutation Database at aims to list all variants and their effect. This update reports on 94 variants. We examined 35 novel and 34 known mutations by site-directed mutagenesis and transient expression in COS-7 cells or HEK293T cells. Each of these mutations was given a severity rating using a previously published system, based on the level of acid a-glucosidase activity in medium and transfected cells and on the quantity and quality of the different molecular mass species in the posttranslational modification and transport of acid a-glucosidase. This approach enabled to classify 55 missense mutations as pathogenic and 13 as likely nonpathogenic. Based on their nature and the use of in silico analysis (Alamut (R) software), 12 of the additional 25 novel mutations were predicted to be pathogenic including 4 splicing mutations, 6 mutations leading to frameshift, and 2 point mutations causing stop codons. Seven of the additional mutations were considered nonpathogenic (4 silent and 3 occurring in intron regions), and 6 are still under investigation. Hum Mutat 33:11611165, 2012. (c) 2012 Wiley Periodicals, Inc.
引用
收藏
页码:1161 / 1165
页数:5
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