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
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Citações na Scopus
61
Tipo de produção
article
Data de publicação
2012
Título da Revista
ISSN da Revista
Título do Volume
Editora
WILEY
Autores
KROOS, Marian
HOOGEVEEN-WESTERVELD, Marianne
MICHELAKAKIS, Helen
POMPONIO, Robert
PLOEG, Ans Van der
HALLEY, Dicky
REUSER, Arnold
Citação
HUMAN MUTATION, v.33, n.8, p.1161-1165, 2012
Resumo
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.
Palavras-chave
GAA, Pompe disease, alpha-glucosidase, acid maltase, glycogenosis, lysosomal storage disorder
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