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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
Author(s) -
Kroos Marian,
HoogeveenWesterveld Marianne,
Michelakakis Helen,
Pomponio Robert,
Van der Ploeg Ans,
Halley Dicky,
Reuser Arnold,
AugoustidesSavvopoulou Persephone,
Ausems Margreet,
Llona Jose Barcena,
Bautista Lorite Juan,
van der Beek Nadine,
Bonafe Luisa,
Cuk Mario,
D'Hooghe Marc,
Engelen Baziel,
Farouk A.,
Fumic K.,
GarciaDelgado E.,
Herzog Andreas,
Hurst J.,
Jones Simon,
Kariminejad M. H.,
Küçükçongar Aynur,
Lissens W.,
Lund Allan,
MajoorKrakauer Danielle,
Kumamoto Shingo,
Maravi E.,
Marie Suely,
Mengel Eugen,
Mavridou Irene,
Munteis Olivas E.,
Najmabadi H.,
Okumiya Toshika,
Peric Stojan,
Paschke Eduard,
Plecko Barbara,
Robberecht Wim,
Serdaroglu Piraye,
Shboul Mohammad,
Tansek Mojca Zerjav,
Tarnutzer A.,
Stojanovic Vidosava Rakocevic,
TylkiSzymanska Anna,
Venâncio Maria,
Verhoeven Kristof
Publication year - 2012
Publication title -
human mutation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 162
eISSN - 1098-1004
pISSN - 1059-7794
DOI - 10.1002/humu.22108
Subject(s) - biology , frameshift mutation , genetics , missense mutation , mutation , gene , in silico , point mutation , exon , mutagenesis , intron , rna splicing , microbiology and biotechnology , rna
Pompe disease is an autosomal recessive lysosomal glycogen storage disorder, characterized by progressive muscle weakness. Deficiency of acid α-glucosidase (EC; 3.2.1.20/3) can be caused by numerous pathogenic variants in the GAA gene. The Pompe Disease Mutation Database at http://www.pompecenter.nl 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 α-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 α-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® 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.