Communicated by Elizabeth F. Neufeld
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†
Article first published online: 29 MAY 2012
© 2012 Wiley Periodicals, Inc.
Volume 33, Issue 8, pages 1161–1165, August 2012
How to Cite
Kroos, M., Hoogeveen-Westerveld, M., Michelakakis, H., Pomponio, R., Van der Ploeg, A., Halley, D., Reuser, A., GAA Database Consortium:, Augoustides-Savvopoulou, P., Ausems, M., Llona, J. B., Bautista Lorite, J., van der Beek, N., Bonafe, L., Cuk, M., D'Hooghe, M., Engelen, B., Farouk, A., Fumic, K., Garcia-Delgado, E., Herzog, A., Hurst, J., Jones, S., Kariminejad, M. H., Küçükçongar, A., Lissens, W., Lund, A., Majoor-Krakauer, D., Kumamoto, S., Maravi, E., Marie, S., Mengel, E., Mavridou, I., Munteis Olivas, E., Najmabadi, H., Okumiya, T., Peric, S., Paschke, E., Plecko, B., Robberecht, W., Serdaroglu, P., Shboul, M., Tansek, M. Z., Tarnutzer, A., Stojanovic, V. R., Tylki-Szymanska, A., Venâncio, M. and Verhoeven, K. (2012), 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. Hum. Mutat., 33: 1161–1165. doi: 10.1002/humu.22108
- Issue published online: 13 JUL 2012
- Article first published online: 29 MAY 2012
- Manuscript Accepted: 16 APR 2012
- Manuscript Received: 10 JAN 2012
- European Union (health F2/2008 grant agreement 201678); Genzyme, a Sanofi company, Cambridge, Massachusetts
- Pompe disease;
- acid maltase;
- lysosomal storage disorder
Pompe disease is an autosomal recessive lysosomal glycogen storage disorder, characterized by progressive muscle weakness. Deficiency of acid α-glucosidase (EC; 22.214.171.124/3) 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. Hum Mutat 33:1161–1165, 2012. © 2012 Wiley Periodicals, Inc.