Molecular genetics of Pompe disease: a comprehensive overview

Abstract

Pompe disease (PD) is an autosomal recessive lysosomal disorder caused by the deficient activity of acid alpha-glucosidase (GAA) enzyme due to mutations in the GAA gene. The enzymatic deficiency leads to the accumulation of glycogen within the lysosomes. Clinically, the disease has been classically classified in infantile and childhood/adult forms. The GAA gene has been localized to chromosome 17q25.2-q25.3 and to date, 582 mutations distributed throughout the whole gene have been reported (HGMD: http://www.hgmd.cf.ac.uk/ac/). All types of mutations have been described; missense variants are the most frequent type followed by small deletions. Most GAA mutations are private or found in a small number of families. However, an exception is represented by the c.-32-13T>G splice mutation that is very common in patients of Caucasian origin affected by the childhood/adult form of the disease, with an allelic frequency ranging from 40% to 70%. In this article, we review the spectrum of GAA mutations, their distribution in different populations, and their classification according to their impact on GAA splicing process, protein expression and activity. In addition, whenever possible, we discuss the phenotype/genotype correlation. The information collected in this review provides an overview of the molecular genetics of PD and can be used to facilitate diagnosis and genetic counseling of families affected by this disorder.

Keywords: GAA mutations; Pompe disease; phenotype/genotype correlation.

Figure 1

Frequency of GAA mutant alleles reported in the HGMD-http://www.hgmd.cf.ac.uk/ac/ classified by mutation type. GAA, acid alpha-glucosidase.

Figure 2

Frequency of GAA mutant alleles reported in the Pompe Disease Mutation Database, available at http://www.pompecenter.nl classified according to their functional impact on GAA. GAA, acid alpha-glucosidase.

Figure 3

GAA mRNA splicing isoforms expressed in cultured fibroblasts. (A) Schematic representation of the 5' region of the GAA gene (exons 1 to 3). The position of the c.-32-13T>G mutation is highlighted in red. The cryptic splice sites, located 35 nt downstream from the normal donor splice site of exon 1 and at 60 nt upstream from the donor site of exon 2, are shown as c1 and c2, respectively. The presence of the c.-32-13T>G mutation abrogates the binding of the U2AF65 splicing factor. (B) Schematic list of the GAA mRNA species expressed in human fibroblasts. Normal spliced GAA mRNA (N) and splicing species SV2 and SV3 are detected both in fibroblasts from patients carrying the c.-32-13T>G variant and healthy controls. In patients vs. controls samples, however, the relative abundance of the various splicing isoforms is different. While N is the main mRNA species expressed in normal cells, SV2 and SV3 are the main species detected in cells from patients bearing the c.-32-13T>G variant. GAA, acid alpha-glucosidase.