Original articleMutations in the gene encoding cytosolic β-glucosidase in Gaucher disease☆
Section snippets
PCR reactions and sequencing
Primers designed to amplify the entire coding region of GBA3 are listed in Table I.
We brought 1 to 4 μL of genomic DNA, 2.5 μL 20× PCR buffer (0.67 mol/L Tris, pH8.8; 0.166 mol/L [NH4]2SO4; 0.067 mol/L MgCl2; 1.7 mg/mL bovine serum albumin), 1.25 μL of a solution containing 10 mmol/L of each deoxyribonucleoside triphosphate, 1 μL of forward primer (100 ng/μL), 1 μL of reverse primer (100 ng/μL), and 0.15 μL of Taq polymerase to a final volume of 50 μL with the addition of water. The reaction
Results
We sequenced the complete coding sequences and 350 base pairs upstream from the start of transcription of the GBA3 gene of 1 normal individual and 11 patients with Gaucher disease. Four polymorphic sites were identified: a rare c.316 G→A substitution (aspartic acid 106 asparagine); a c.1353A→G substitution that is synonymous for tyrosine 451; a c.1368T→A substitution that converts tyrosine 456 to a stop codon and a substitution of a T for c.1540–541 AG in the 3′ untranslated region. Another
Discussion
It has become apparent that a great deal of phenotypic variability exists among “homozygotes” for single-gene diseases. In some instances it has been possible to show that such heterogeneity is a result of polymorphism in interacting genes. For example, glucose-6-phosphate dehydrogenase–deficient infants in whom severe neonatal jaundice develops have usually coinherited the uridine diphosphate–glucuronosyltansferase promoter polymorphism associated with Gilbert disease.16 The presence of factor
References (17)
Discrepancies between genotype and phenotype in hematologyAn important frontier
Blood
(2001)Gaucher disease
Adv Genet
(1995)- et al.
Viral infections and phenotypic heterogeneity in Gaucher disease
Blood Cells Mol Dis
(2001) - et al.
Purification and characterization of a cytosolic broad specificity beta-glucosidase from human liver
J Biol Chem
(1981) - et al.
Differentiation of beta-glucocerebrosidase from beta-glucosidase in human tissues using sodium taurocholate
Arch Biochem Biophys
(1976) - et al.
Solubilization of glucocerebrosidase from human placenta and demonstration of a phospholipid requirement for its catalytic activity
Biochem Biophys Res Commun
(1976) Venous thrombosisA multicausal disease
Lancet
(1999)- et al.
Phenotypic manifestations of Gaucher diseaseClinical features in 48 biochemically verified Type I patients and comment on Type II patients
Cited by (18)
Infection of maize inbred B73 by Ustilago maydis and Fusarium proliferatum triggers differential expression of the β-glucosidase genes
2018, Physiological and Molecular Plant PathologyPilot study of newborn screening for six lysosomal storage diseases using Tandem Mass Spectrometry
2016, Molecular Genetics and MetabolismKlotho-Related Protein KLrP: Structure and Functions
2016, Vitamins and HormonesCitation Excerpt :The KLrP and GBA2 to GD connection have been examined by several research groups. Beutler, Beutler, and West (2004) examined whether polymorphisms in KLrP are related to GD. They found four single-nucleotide substitutions in KLrP from GD patients; however, these mutations were not related to GD phenotypes.
The cytosolic β-glucosidase GBA3 does not influence type 1 Gaucher disease manifestation
2011, Blood Cells, Molecules, and DiseasesCitation Excerpt :Disease severity, as measured with a commonly employed composite score, did not correlate with the GBA3 1368A haplotype of the type 1 Gaucher disease patients examined. Our findings support earlier observations by Beutler and colleagues and substantiate their conclusion that GBA3 does not influence clinical severity of type I Gaucher disease [21]. The common 1368T→A mutation in the GBA3 gene may contribute to the wide range of cytosolic β-glucosidase activity measured in human leukocytes [20].
Glycobiology in the cytosol: The bitter side of a sweet world
2009, Biochimica et Biophysica Acta - General SubjectsKlotho-related protein is a novel cytosolic neutral β- glycosylceramidase
2007, Journal of Biological ChemistryCitation Excerpt :It is not clear whether any specific disease is associated with a deficiency of KLrP. Although polymorphisms were found in the gene of KLrP (GBA3) of patients with Gaucher disease, it seems unlikely that they are related to the variable phenotype of patients with this disease (37). Interestingly, Korkotian et al. (38) reported that GlcCer could escape from lysosomes in type 2 and 3 Gaucher disease patients and might affect the Ca2+ homeostasis of neuronal cells by modulating the ryanodine receptor in the ER (38).
- ☆
Supported by National Institutes of Health grants DK061370 and RR00833 and by the Stein Endowment Fund.