Glucocerebrosidase Mutations in Gaucher Disease

Abstract

Background: Thirty-six mutations that cause Gaucher disease, the most common glycolipid storage disorder, are known. Although both alleles of most patients with the disease contain one of these mutations, in a few patients one or both disease-producing alleles have remained unidentified. Identification of mutations in these patients is useful for genetic counseling. Materials and Methods: The DNA from 23 Gaucher disease patients in whom at least one glucocerebrosidase allele did not contain any of the 36 previously described mutations has been examined by single strand conformation polymorphism (SSCP) analysis, followed by sequencing of regions in which abnormalities were detected. Results: Eight previously undescribed mutations were detected. In exon 3, a deletion of a cytosine at cDNA nt 203 was found. In exon 6, three missense mutations were identified: a C-A transversion at cDNA nt 644 (Ala176-*Asp), a C-)A transversion at cDNA nt 661 that resulted in a (Pro'82-Thr), and a G-A transition at cDNA nt 721 (Gly202-3Arg). Two missense mutations were found in exon 7: a G-A transition at cDNA nt 887 (Arg257-Gln) and a C-T at cDNA nt 970 (Arg285__Cys). Two missense mutations were found in exon 9: a T-)G at cDNA nt 1249 (Trp378-* Gly) and a G-+A at cDNA nt 1255 (Asp380-+Asn). In addition to these disease-producing mutations, a silent C-)G transversion at cDNA nt 1431, occurring in a gene that already contained the 1226G mutation, was found in one family. Conclusions: The mutations described here and previously known can be classified as mild, severe, or lethal, on the basis of their effect on enzyme production and on clinical phenotype, and as polymorphic or sporadic, on the basis of the haplotype in which they are found. Rare mutations such as the new ones described here are sporadic in nature.

Next-generation sequencing reveals substantial genetic contribution to dementia with Lewy bodies

“…The p.D448H [p.D409H], p.N409S [p.N370S] and p.R296Q [p.R257Q] GBA mutations have been associated with Gaucher disease and parkinsonism, likely due to impaired lysosomal protein degradation (Beutler, et al, 1994; Choi, et al, 2012; Sidransky, 2004; Sidransky, et al, 2009). The GBA p.E365K [p.E326K] mutation is considered a mild mutation as it has been demonstrated to reduce rather than abolish glucocerebrosidase enzyme activity (Alcalay, et al, 2015; Malini, et al, 2014).…”

Type 2 Gaucher disease: the collodion baby phenotype revisited

“…This 55 bp segment is ordinarily absent in the pseudogene. An uncommon mutation, R257Q,16 was identified on the second allele. This mutation obliterates a BsmAI site in exon 7, and its presence was confirmed by restriction digestion.…”

Glucocerebrosidase mutations among chinese neuronopathic and non-neuronopathic Gaucher disease patients

“…Mutation Y205C was found in the heterozygous form with mutation L444P in patient LR who has severe developmental delay and hematological and orthopedic complications. In conjunction with mutation L444P previously described as a severe mutation [Beutler et al, 1994], the L444P/ Y205C genotype appears to result in poor prognosis.…”

“…NciI and BsaJI RFLP analysis was used to detect mutations L444P, G202R, and D409H [Tsuji et al, 1987;Beutler et al, 1994;Theophilus et al, 1989]. Mutation 754A (F213I) [Kawame and Eto, 1991] and the recombinant allele (recNciI), containing mutations L444P, A456P, and V460V [Latham et al, 1990;Zimran et al, 1990], were detected by sequence analysis using the ABI Prism TM 377 DNA sequencer and the BigDye Terminator Cycle sequencing kit (Perkin Elmer Applied Systems, Foster City, CA), in accordance with the manufacturer's specifications.…”