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Title: High frequency of mutation G377S in Brazilian type 3 Gaucher disease patients
Authors: Rozenberg, Roberto
Araujo, Fernando T.
Fox, Deborah Catherine
Aranda, Paulo Cesar
Nonino, Alexandre
Micheletti, Cecília [UNIFESP]
Martins, Ana Maria [UNIFESP]
Cravo, Renata
Sobreira, Elisa
Pereira, Lygia da Veiga
Universidade de São Paulo (USP)
Hosp Evangel Londrina
Hosp Base Distrito Fed
Universidade Federal de São Paulo (UNIFESP)
Santa Casa São Paulo
Keywords: Gaucher disease
GBA gene
allele dose effect
Issue Date: 1-Sep-2006
Publisher: Assoc Bras Divulg Cientifica
Citation: Brazilian Journal of Medical and Biological Research. São Paulo: Assoc Bras Divulg Cientifica, v. 39, n. 9, p. 1171-1179, 2006.
Abstract: Gaucher disease (GD), the most prevalent lysosome storage disorder, presents an autosomal recessive mode of inheritance. It is a paradigm for therapeutic intervention in medical genetics due to the existence of effective enzyme replacement therapy. We report here the analysis of GD in 262 unrelated Brazilian patients, carried out in order to establish the frequency of the most common mutations and to provide prognostic information based on genotype-phenotype correlations. Among 247 type 1 GD patients, mutation N370S was detected in 47% of all the alleles, but N370S/N370S homozygosity was found in only 10% of the patients, a much lower frequency than expected, suggesting that most individuals presenting this genotype may not receive medical attention. Recombinant alleles were detected at a high frequency: 44% of the chromosomes bearing mutation L444P had other mutations derived from the pseudogene sequence, present in 25% of patients. Three neuronopathic type 2 patients were homozygous for L444P, all presenting additional mutations (E326K or recombinant alleles) that probably lead to the more severe phenotypes. Six children, classified as type 1 GD patients, had a L444P/L444P genotype, showing that neuronopathic symptoms may only manifest later in life. This would indicate the need for a higher treatment dose during enzyme replacement therapy. Finally, mutation G377S was present in 4 homozygous type 1 patients and also in compound heterozygosity in 5 (42%) type 3 patients. These findings indicate that G377S cannot be unambiguously classified as mild and suggest an allele-dose effect for this mutation.
ISSN: 0100-879X
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