Glucocerebrosidase mutations in Gaucher disease.
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TLDR
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, onThe basis of the haplotype in which they are found.Abstract:
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. 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. 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 (Pro182→Thr), and a G→A transition at cDNA nt 721(Gly202→Arg). 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. 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.read more
Citations
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Journal ArticleDOI
Gaucher disease: mutation and polymorphism spectrum in the glucocerebrosidase gene (GBA).
TL;DR: The spectrum of GBA mutations and their distribution in the patient population, evolutionary conservation, clinical presentations, and how they may affect the structure and function of glucocerebrosidase are discussed.
Journal ArticleDOI
ER retention and degradation as the molecular basis underlying Gaucher disease heterogeneity
Idit Ron,Mia Horowitz +1 more
TL;DR: The results strongly suggest that mutant glucocerebrosidase variants present variable levels of ER retention and undergo ER-associated degradation in the proteasomes, one of the factors that determine GD severity.
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Hematologically important mutations: Gaucher disease.
Ernest Beutler,Terri Gelbart +1 more
Journal ArticleDOI
Glucocerebrosidase gene mutations in patients with type 2 Gaucher disease.
Deborah L. Stone,Nahid Tayebi,Eduard Orvisky,Barbara K. Stubblefield,Victor Madike,Ellen Sidransky +5 more
TL;DR: This report constitutes the most comprehensive molecular study to date of type 2 Gaucher disease, and it demonstrates that there is significant phenotypic and genotypic heterogeneity among patients with type 2 gaucher disease.
Journal ArticleDOI
2 Gaucher's disease: molecular, genetic and enzymological aspects
TL;DR: Clarification of genotype/phenotype relationships and the identification of modifier loci that impact on Gaucher's disease phenotypes remain a critical area for research.
References
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Journal ArticleDOI
The human glucocerebrosidase gene and pseudogene : structure and evolution
TL;DR: The sequence of the entire human gene encoding beta-glucocerebrosidase and that of the associated pseudogene is reported to facilitate development of methods for diagnosis of Gaucher disease at the molecular level.
Journal ArticleDOI
Gaucher disease. Clinical, laboratory, radiologic, and genetic features of 53 patients.
TL;DR: Repeated follow-up examinations in 29 patients revealed that in the majority of the patients, progression of the disease occurs during childhood, adolescence, or early adulthood with a marked tendency for stabilization thereafter, suggesting that Gaucher disease in most of the Patients is not a relentless progressive disorder but a rather stable disorder during adulthood.
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A mutation in the human glucocerebrosidase gene in neuronopathic Gaucher's disease.
Shoji Tsuji,Prabhakara V. Choudary,Brian M. Martin,Barbara K. Stubblefield,June A. Mayor,John A. Barranger,Edward I. Ginns +6 more
TL;DR: The high frequency of this mutation (444leucine----proline) in patients with neuronopathic Gaucher's disease, detectable by the NciI RFLP, may be of value in the identification of patients who will have the neurologic sequelae of Gaucher’s disease.
Journal ArticleDOI
Animal model of Gaucher's disease from targeted disruption of the mouse glucocerebrosidase gene.
Victor L. J. Tybulewicz,Victor L. J. Tybulewicz,Michel L. Tremblay,Michel L. Tremblay,LaMarca,Rob Willemsen,B. K. Stubblefield,S. Winfield,B. Zablocka,E. Sidransky,Brian M. Martin,Sing-Ping Huang,K. A. Mintzer,Heiner Westphal,Richard C. Mulligan,Edward I. Ginns +15 more
TL;DR: An animal model for Gaucher's disease is generated by creating a null allele in embryonic stem cells through gene targeting and using these genetically modified cells to establish a mouse strain carrying the mutation.
Journal ArticleDOI
Gaucher's disease.
TL;DR: Gaucher's disease is an autosomal recessive disorder caused by a deficiency of glucocerebrosidase (glucosylceramidase), the enzyme required for the lysosomal degradation of lipids containing covalently bound sugars (glycolipids) as discussed by the authors.