title: Molecular and functional characterization of eight novel GAA mutations in Italian infants with Pompe disease.
abstract: We characterized 29 unrelated patients presenting with the severe form of Pompe disease (Glycogen Storage Disease Type II, acid maltase deficiency) and identified 26 pathogenic mutations divided over 28 different genotypes. Among the eight new mutations, five were exonic point mutations (c.572A>G, c.1124G>T, c.1202A>G, c.1564C>G and c.1796C>A) leading to codon changes (p.Y191C, p.R375L, p.Q401R, p.P522A and p.S599Y); two were intronic point mutations (c.-32-3C>A and c.1636+5G>C) affecting mRNA processing; one was a single base deletion (c.742delC) generating a truncated protein (p.L248PfsX20). A comprehensive evaluation, based on different methodological approaches, confirmed the detrimental effect of the eight mutations on the protein and its function. Structural alterations potentially induced by the five missense mutations were also predicted through visual inspection of the atomic model of the GAA protein, in terms of both function and spatial orientation of specific residues as well as disturbance generated by amino acid substitutions. Although the remarkable heterogeneity of the mutational spectrum in Pompe disease was already known, our data demonstrate and confirm the power of molecular and functional analysis in predicting the natural course of Pompe disease.
authors.affiliation: Unità di Malattie Metaboliche, IRCCS Burlo Garofolo, Trieste, Italy.
authors.forename: M G
authors.initials: MG
authors.lastname: Pittis
authors.forename: M
authors.initials: M
authors.lastname: Donnarumma
authors.forename: A L E
authors.initials: AL
authors.lastname: Montalvo
authors.forename: S
authors.initials: S
authors.lastname: Dominissini
authors.forename: M
authors.initials: M
authors.lastname: Kroos
authors.forename: C
authors.initials: C
authors.lastname: Rosano
authors.forename: M
authors.initials: M
authors.lastname: Stroppiano
authors.forename: M G
authors.initials: MG
authors.lastname: Bianco
authors.forename: M A
authors.initials: MA
authors.lastname: Donati
authors.forename: G
authors.initials: G
authors.lastname: Parenti
authors.forename: A
authors.initials: A
authors.lastname: D'Amico
authors.forename: G
authors.initials: G
authors.lastname: Ciana
authors.forename: M
authors.initials: M
authors.lastname: Di Rocco
authors.forename: A
authors.initials: A
authors.lastname: Reuser
authors.forename: B
authors.initials: B
authors.lastname: Bembi
authors.forename: M
authors.initials: M
authors.lastname: Filocamo
mesh_terms: D000818:Animals; D019556:COS Cells; D002675:Child, Preschool; D002522:Chlorocebus aethiops; D004252:DNA Mutational Analysis; D005091:Exons; D017353:Gene Deletion; D006009:Glycogen Storage Disease Type II / Q000235:genetics*; D006801:Humans; D007223:Infant; D007438:Introns; D008958:Models, Molecular; D009154:Mutation; D020125:Mutation, Missense; D017354:Point Mutation; D000520:alpha-Glucosidases / Q000737:chemistry / Q000235:genetics*
chemical_list: C509951:GAA protein, human; D000520:alpha-Glucosidases