title: Novel insertion mutation in a non-Jewish Caucasian type 1 Gaucher disease patient.
abstract: Gaucher disease is the most prevalent lysosomal storage disorder. It is autosomalrecessive, resulting in lysosomal glucocerebrosidase deficiency. Three clinical forms of Gaucher disease have been described: type 1 (nonneuronopathic), type 2 (acute neuronopathic), and type 3 (subacute neuronopathic). We performed PCR-thermal cycle sequence analysis of glucocerebrosidase genomic DNA and identified a novel mutation in a non-Jewish type 1 Gaucher disease patient. It is a C insertion in exon 3 at cDNA nucleotide position 122 and genomic nucleotide position 1626. This mutation causes a frameshift and, subsequently, four of the five codons immediately downstream of the insertion were changed while the sixth was converted to a stop codon, resulting in premature termination of protein translation. The 122CC insertion abolishes a Cac81 restriction endonuclease cleavage site, allowing a convenient and reliable method for detection using RFLP analysis of PCR-amplified glucocerebrosidase genomic DNA. The mutation in the other Gaucher allele was found to be an A-->G substitution at glucocerebrosidase cDNA nucleotide position 1226 that so far has only been reported among type 1 Gaucher disease patients. Since mutation 122CC causes a frameshift and early termination of protein translation, it most likely results in a meaningless transcript and subsequently no residual glucocerebrosidase enzyme activity. We speculate that mutation 122CC may result in a worse prognosis than mutations associated with partial activity. When present in the homozygous form, it could be a lethal allele similar to what has been postulated for the other known insertion mutation, 84GG. Our patient, who is a compound heterozygote 122CC/1226G, has moderately severe type 1 Gaucher disease. Her clinical response to Ceredase therapy that began 31 months ago has been favorable, though incomplete.
authors.affiliation: Department of Biology, University of Victoria, British Columbia, Canada.
authors.forename: F Y
authors.initials: FY
authors.lastname: Choy
authors.forename: M L
authors.initials: ML
authors.lastname: Humphries
authors.forename: P
authors.initials: P
authors.lastname: Ferreira
mesh_terms: D000328:Adult; D000483:Alleles; D002478:Cells, Cultured; D018388:Codon, Terminator; D018076:DNA, Complementary / Q000235:genetics; D005091:Exons; D005260:Female; D005347:Fibroblasts; D016368:Frameshift Mutation; D005776:Gaucher Disease / Q000175:diagnosis / Q000235:genetics*; D005962:Glucosylceramidase / Q000235:genetics*; D006801:Humans; D016254:Mutagenesis, Insertional; D017354:Point Mutation; D016133:Polymerase Chain Reaction; D012150:Polymorphism, Restriction Fragment Length; D014176:Protein Biosynthesis; D017422:Sequence Analysis, DNA
chemical_list: D018388:Codon, Terminator; D018076:DNA, Complementary; D005962:Glucosylceramidase