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Characterization of two novel GBA mutations causing Gaucher disease that lead to aberrant RNA species by using functional splicing assays

The correct identification of disease‐causing mutations from the background of harmless nucleotide polymorphisms/substitutions has become a critical issue in the investigation of human genetic diseases. Here, we describe two novel disease‐causing splicing mutations in the glucocerebrosidase gene, g....

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Published in:Human mutation 2006-01, Vol.27 (1), p.119-119
Main Authors: Dominissini, Silvia, Buratti, Emanuele, Bembi, Bruno, Baralle, Marco, Pittis, Maria Gabriela
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Buratti, Emanuele
Bembi, Bruno
Baralle, Marco
Pittis, Maria Gabriela
description The correct identification of disease‐causing mutations from the background of harmless nucleotide polymorphisms/substitutions has become a critical issue in the investigation of human genetic diseases. Here, we describe two novel disease‐causing splicing mutations in the glucocerebrosidase gene, g.4252C>G and g.4426A>G, that have been found in two patients affected by Gaucher disease. The g.4252C>G substitution occurred in intron 5 and was located 12 nucleotides upstream of exon 6 acceptor site whilst the g.4426A>G mutation was located within this exon, 12 nucleotides upstream of the donor site. An in silico analysis suggested that both mutations could have altered the splicing process of exon 6 by creating a novel acceptor and donor site, respectively. However, because the wild‐type acceptor and donor sites of exon 6 were not apparently affected, the severity of both mutations could not be established by simple sequence analysis alone. Nonetheless, the use of minigene functional assays to complement transcript analysis of patient fibroblasts shows that both mutations cause the almost complete switch of splice site usage from the wild‐type to the newly‐created ones, thus providing a functional explanation for the appearance of disease. © 2005 Wiley‐Liss, Inc.
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ispartof Human mutation, 2006-01, Vol.27 (1), p.119-119
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subjects Aged
Alternative Splicing - genetics
Disease
DNA Mutational Analysis
Enzymes
Exons - genetics
Female
Fibroblasts - metabolism
functional splicing assay
Gaucher disease
Gaucher Disease - enzymology
Gaucher Disease - genetics
GBA gene
Genetic disorders
Glucosylceramidase - genetics
HeLa Cells
Humans
Male
Middle Aged
Mutation
Mutation - genetics
Nervous system
Patients
RNA Splice Sites - genetics
RNA, Messenger - genetics
RNA, Messenger - metabolism
splicing mutations
Thrombocytopenia
Tumor Cells, Cultured
title Characterization of two novel GBA mutations causing Gaucher disease that lead to aberrant RNA species by using functional splicing assays
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