title: Gaucher disease: A G+1----A+1 IVS2 splice donor site mutation causing exon 2 skipping in the acid beta-glucosidase mRNA.
abstract: Gaucher disease is the most frequent lysosomal storage disease and the most prevalent Jewish genetic disease. About 30 identified missense mutations are causal to the defective activity of acid beta-glucosidase in this disease. cDNAs were characterized from a moderately affected 9-year-old Ashkenazi Jewish Gaucher disease type 1 patient whose 80-year-old, enzyme-deficient, 1226G (Asn370----Ser [N370S]) homozygous grandfather was nearly asymptomatic. Sequence analyses revealed four populations of cDNAs with either the 1226G mutation, an exact exon 2 (delta EX2) deletion, a deletion of exon 2 and the first 115 bp of exon 3 (delta EX2-3), or a completely normal sequence. About 50% of the cDNAs were the delta EX2, the delta EX2-3, and the normal cDNAs, in a ratio of 6:3:1. Specific amplification and characterization of exon 2 and 5' and 3' intronic flanking sequences from the structural gene demonstrated clones with either the normal sequence or with a G+1----A+1 transition at the exon 2/intron 2 boundary. This mutation destroyed the splice donor consensus site (U1 binding site) for mRNA processing. This transition also was present at the corresponding exon/intron boundary of the highly homologous pseudogene. This new mutation, termed "IVS2 G+1----A+1," is the first splicing mutation described in Gaucher disease and accounted for about 3.4% of the Gaucher disease alleles in the Ashkenazi Jewish population. The occurrence of this "pseudogene"-type mutation in the structural gene indicates the role of acid beta-glucosidase pseudogene and structural gene rearrangements in the pathogenesis of this disease.
authors.affiliation: Department of Pediatrics, Mount Sinai School of Medicine, New York.
authors.forename: G S
authors.initials: GS
authors.lastname: He
authors.forename: G A
authors.initials: GA
authors.lastname: Grabowski
mesh_terms: D000368:Aged; D001483:Base Sequence; D002648:Child; D002675:Child, Preschool; D005091:Exons; D005260:Female; D005776:Gaucher Disease / Q000201:enzymology / Q000235:genetics*; D017353:Gene Deletion; D005796:Genes; D005838:Genotype; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D009154:Mutation; D009838:Oligodeoxyribonucleotides; D010375:Pedigree; D016133:Polymerase Chain Reaction / Q000379:methods; D011544:Pseudogenes; D012326:RNA Splicing; D012333:RNA, Messenger / Q000235:genetics*; D001617:beta-Glucosidase / Q000235:genetics*
chemical_list: D009838:Oligodeoxyribonucleotides; D012333:RNA, Messenger; D001617:beta-Glucosidase