High frequency of mutation G377S in Brazilian type 3 Gaucher disease patients

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.

Mapping the genetic and clinical characteristics of Gaucher disease in the Iberian Peninsula

“…However, this mutation in compound heterozygosity with two missense mutations, G195W or R463C (G377S/G195W or G377S/R463C genotypes), was found in patients who developed neurological symptoms during childhood (type 3 GD patients). Similar observations were reported in patients from Brazil, who were compound heterozygous with one mutation being G377S [38]. Another interesting observation was the combination of the double-mutant allele [E323K;N188S] with two mutations that are considered severe: D409H and L444P.…”

Gaucher disease: single gene molecular characterization of one-hundred Indian patients reveals novel variants and the most prevalent mutation

“…Several ethnicity specific mutations have been observed in the GD. For instance, the mutation p.Gly416Ser is observed in high frequency in Brazilian GD type 3 patients [22]. The mutations p.Leu483Pro and p.Phe252Ile are relatively common in Japanese GD patients [23, 24].…”

Characteristics of 26 patients with type 3 Gaucher disease: A descriptive analysis from the Gaucher Outcome Survey

“…The GD3 population included in this analysis originates from Brazil, the United Kingdom, Israel, and the United States, none of which have been previously noted for having a particularly high prevalence of GD3 [14] , [29] , [30] . In this analysis, 3 of 33 (9.1%) patients enrolled in GOS in Brazil had GD3, compared with a previous report of 5% [29] , although absolute numbers were small.…”

“…The GD3 population included in this analysis originates from Brazil, the United Kingdom, Israel, and the United States, none of which have been previously noted for having a particularly high prevalence of GD3 [14] , [29] , [30] . In this analysis, 3 of 33 (9.1%) patients enrolled in GOS in Brazil had GD3, compared with a previous report of 5% [29] , although absolute numbers were small. Given the low patient numbers involved, the percentage of patients reported as having GD3 in GOS (2.7%) is similar to that reported by other registry studies (5%), which typically include countries known to have higher prevalence rates of GD3, such as Sweden, Egypt, China, India, Korea, and Japan [4] , [5] , [6] , [7] , [8] , [9] .…”