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

Abstract

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.

Copackaged AAV9 Vectors Promote Simultaneous Immune Tolerance and Phenotypic Correction of Pompe Disease

“…Haploinsufficiency of GAA does not result in Pompe disease, the onset of disease symptoms inversely correlates with GAA quality and quantity, and even 2-3% of normal activity has shown to be clinically relevant in outcome measures for similar protein deficiencies, such as hemophilia B. 48,72,73 Considering also that the duration of these studies was 8 weeks and the ability for AAV9 to remain in circulation for prolonged periods, transduction may increase over time. 24 Based on evidence of central and peripheral nervous system pathology, adequate transgene expression within these tissues will be necessary to achieve long-term therapeutic benefit, regardless of the onset of disease progression.…”

Profile of alglucosidase alfa in the treatment of Pompe disease: safety, efficacy, and patient acceptability

“…[20][21][22][23] Currently, the "gold standard" diagnostic for Pompe disease is the GAA assay performed on skin fibroblasts or muscle biopsy followed by DNA analysis 24,25 with detection of homozygote or compound heterozygote mutations in the GAA gene. To date more than 300 different mutations have been found, 26 without strict genotype-phenotype correlation.…”

Laboratory studies and Pompe disease: from suspicion to therapy monitoring

“…Последний является предпочтительным и наибо-лее часто используемым. Со времени клонирования гена GAA (OMIM: 606800), кодирующего кислую α-глюкозидазу, описано более 350 патогенных мутаций этого гена [17]. Большинство больных являются ком-паунд-гетерозиготными (т. е. несут 2 различные пато-генные мутации).…”