Mutation analysis of Gaucher disease patients from Argentina: High prevalence of the RecNciI mutation

Abstract

Gaucher disease (GD) is caused by a deficiency of beta-glucocerebrosidase activity mainly due to mutations in the gene coding for the enzyme. More than 100 mutations have been identified to date and their frequencies have been established in several populations, including Ashkenazi Jews, among whom the disease is particularly prevalent. In order to study the molecular pathology of the disease in patients from Argentina, we conducted a systematic search for mutations in the glucocerebrosidase gene. Genomic DNA from 31 unrelated GD patients was screened for seven previously described mutations: N370S (1226A-->G), L444P (1448T-->C), D409H (1342G-->C), R463C (1504C-->T), 1263de155, RecNciI, and RecTL. This allowed the identification of 77.4% of the GD alleles: N370S and RecNciI were the most prevalent mutations found (46.8% and 21% respectively). Southern analysis demonstrated three distinct patterns for the RecNciI alleles. In order to identify the remaining alleles, the full coding region of the gene, all the splice sites, and part of the promoter region were analyzed by single-strand conformational polymorphism analysis (SSCP) after polymerase chain reaction amplification. This extensive screening allowed the identification of 13 different mutations, accounting for 93% of the total number of GD alleles. Three novel missense mutations, I161S (599T-->G), G265D (911G-->A), and F411I (1348T-->A), were detected. Twelve polymorphic sites within the glucocerebrosidase gene are in complete linkage disequilibrium and define two major haplotypes, "-" and "+". Mutation N370S was always associated with the "-" haplotype, as described in other populations. Interestingly, the RecNciI alleles with the same Southern-blot pattern were always associated with the same haplotype.

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

“…Since some patients may have A456P and lack the silent mutation in V460V, the frequency of RECs in this sample may be even higher. The high frequency of RECs was also described in other countries (9,15). It is generally observed that the RECs have a more severe impact on clinical manifestation than L444P alone (9,(16)(17)(18).…”

Glucosidase acid beta gene mutations in Egyptian children with Gaucher disease and relation to disease phenotypes

“…However, the frequency of Rec alleles in other studies ranged from 3.5% to 21%. [9,13,17] In addition to different ethnicity and sample size, technical differences may explain this variation. [16] Mutation analysis was done in some studies [9] by screening for the most common mutations only by the mismatched PCR amplifi cation technique, which has inherent limitations as additional mutations may result in under-estimation of the frequency of recombinant alleles.…”

Identification of a novel recombinant mutation in Korean patients with Gaucher disease using a long-range PCR approach

“…Although the majority of GBA mutations are missense and non-sense, GBA recombinant alleles have been found at a high frequency in several populations (B24%), [12][13][14][15] but, are very rare in an Ashkenazi Jewish population (B3%). 12,13 In this study, we identified four recombinant alleles among 72 alleles (5.6%) of 36 unrelated Korean GD patients.…”