Naslov
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.

Autori
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, JB ; Bautista Lorite, J ; van der Beek, N ; Bonafe, L ; Ćuk, Mario ; D'Hooghe, M ; Engelen, B ; Farouk, A ; Fumić, Ksenija ; Garcia-Delgado, E, et al.

Izvornik
Human mutation (1059-7794) 33 (2012), 8; 1161-1165

Vrsta, podvrsta i kategorija rada
Radovi u časopisima, članak, znanstveni

Ključne riječi
GAA; Pompe disease; α-glucosidase; acid maltase; glycogenosis; lysosomal storage disease

Sažetak
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.

Izvorni jezik
Engleski

POVEZANOST RADA