scholarly journals Two phosphatidylinositol 4-kinases control lysosomal delivery of the Gaucher disease enzyme, β-glucocerebrosidase

2012 ◽  
Vol 23 (8) ◽  
pp. 1533-1545 ◽  
Author(s):  
Marko Jović ◽  
Michelle J. Kean ◽  
Zsofia Szentpetery ◽  
Gordon Polevoy ◽  
Anne-Claude Gingras ◽  
...  
Keyword(s):  
Gaucher Disease ◽  
Lysosomal Storage Disorder ◽  
Integral Membrane Protein ◽  
Lysosomal Storage ◽  
Trafficking Pathway ◽  
Golgi Compartment ◽  
Phosphatidylinositol 4 ◽  
Endosomal Vesicles ◽  
Membrane Protein Type

Gaucher disease is a lysosomal storage disorder caused by a defect in the degradation of glucosylceramide catalyzed by the lysosomal enzyme β-glucocerebrosidase (GBA). GBA reaches lysosomes via association with its receptor, lysosomal integral membrane protein type 2 (LIMP-2). We found that distinct phosphatidylinositol 4-kinases (PI4Ks) play important roles at multiple steps in the trafficking pathway of the LIMP-2/GBA complex. Acute depletion of phosphatidylinositol 4-phosphate in the Golgi caused accumulation of LIMP-2 in this compartment, and PI4KIIIβ was found to be responsible for controlling the exit of LIMP-2 from the Golgi. In contrast, depletion of PI4KIIα blocked trafficking at a post-Golgi compartment, leading to accumulation of LIMP-2 in enlarged endosomal vesicles. PI4KIIα depletion also caused secretion of missorted GBA into the medium, which was attenuated by limiting LIMP-2/GBA exit from the Golgi by PI4KIIIβ inhibitors. These studies identified PI4KIIIβ and PI4KIIα as important regulators of lysosomal delivery of GBA, revealing a new element of control to sphingolipid homeostasis by phosphoinositides.

scholarly journals TYPE 2 GAUCHER DISEASE: ONSET AND EVOLUTION – CASE REPORT

2015 ◽  
Vol 64 (3) ◽  
pp. 293-296
Author(s):  
Violeta Streanga ◽  
◽  
Cristina Jitareanu ◽  
Irina M. Ciomaga ◽  
Doina Mihaila ◽  
...  
Keyword(s):  
Enzyme Activity ◽  
Gaucher Disease ◽  
Lysosomal Storage Disorder ◽  
Autosomal Recessive ◽  
Disease Onset ◽  
Lysosomal Storage ◽  
Subsequent Evolution ◽  
Dismal Prognosis ◽  
Recessive Transmission

Gaucher disease is the most common lysosomal storage disorder, with autosomal recessive transmission. The disease is due to glucocerebrosidase enzyme deficiency, resulting in accumulation of glucocerebroside in all organs. The diagnosis is established by measuring enzyme activity. Among the clinical forms, type 2 is the rarest and has the most dismal prognosis. We present the case of an infant found at 5 months of age with neurological symptoms and his subsequent evolution with massive hepatosplenomegaly, being diagnosed with type 2 Gaucher disease.

scholarly journals Disease-causing mutations within the lysosomal integral membrane protein type 2 (LIMP-2) reveal the nature of binding to its ligand β-glucocerebrosidase

2009 ◽  
Vol 19 (4) ◽  
pp. 563-572 ◽  
Author(s):  
Judith Blanz ◽  
Johann Groth ◽  
Christina Zachos ◽  
Christina Wehling ◽  
Paul Saftig ◽  
...  
Keyword(s):  
Membrane Protein ◽  
Integral Membrane Protein ◽  
Membrane Protein Type

scholarly journals Gaucher disease: clinical phenotypes and refining GBA mutational spectrum in Thai patients

2021 ◽  
Vol 16 (1) ◽  
Author(s):  
Tim Phetthong ◽  
Thipwimol Tim-Aroon ◽  
Arthaporn Khongkraparn ◽  
Saisuda Noojarern ◽  
Chulaluck Kuptanon ◽  
...  
Keyword(s):  
Gaucher Disease ◽  
Age Of Onset ◽  
Lysosomal Storage ◽  
Pathogenic Variants ◽  
Medical Centers ◽  
Neurologic Involvement ◽  
Therapeutic Research ◽  
Type 3

Abstract Background Gaucher disease (GD) is a rare lysosomal storage disorder, characterized by hepatosplenomegaly and pancytopenia, with or without neurologic involvement. The disorder is categorized into three phenotypes: GD type 1 or nonneuronopathic GD; GD type 2 or acute neuronopathic GD; and GD type 3 or chronic neuronopathic GD. The purposes of this study were to describe clinical characteristics of Thai GD in patients diagnosed and/or followed up during 2010–2018 and to perform re-genotyping including analysis of GBA recombinant alleles which had not been investigated in Thai patients before. Results There were 27 patients from seven medical centers, enrolled in the study. All the cases had pediatric onset. GD3 (44.5%) was the most common phenotype, followed by GD2 (40.7%) and GD1 (14.8%), with one case of neonatal GD. The median age of onset for GD1, GD2, and GD3 was 72, 4 and 12 months, respectively, suggesting relatively earlier onset of GD1 and GD3 in Thai patients. All patients with GD1 and most patients with GD3 received ERT. Four patients with GD3 had ERT followed by HSCT. Patients with GD3 who received no or late ERT showed unfavorable outcomes. We identified 14 variants including two novel (p.S384F and p.W533*) and 12 reported pathogenic variants: p.L483P, p.N409S, p.R159W, p.P305A, p.A175G, p.D448H, p.V414L, IVS2+1G>A, IVS6-1G>C, IVS7+1G>C, IVS9-3C>G, and Rec1a. The p.L483P was the most prevalent allele found in this study, at 66% (33/50 alleles), followed by IVS2+1G>A, Rec1a, and IVS6-1G>C. Twenty-four percent of patients were reassigned with validated genotypes, most of whom (4 of 6) were patients with GD2. The [p.S384F + p.W533*] being compounded with p.L483P, was found in the patient with neonatal GD, suggesting that the p.S384F could potentiate the deleterious effect of the p.W533*, and/or vice versa. Conclusions Neuronopathic GD was strikingly prevalent among Thai affected population. Homozygous p.L483P was the most common genotype identified in Thai patients. Recombinant allele Rec1a and splicing mutations were associated with GD2 and severe cases of GD3. Mutation spectrum could be useful for designing stepwise molecular analysis, genetic screenings in population, and new therapeutic research for neuronopathic GD.

scholarly journals Gaucher disease: clinical phenotypes and refining GBA mutational spectrum in Thai patients

2021 ◽  
Author(s):  
Tim Phetthong ◽  
Thipwimol Tim-Aroon ◽  
Arthaporn Khongkraparn ◽  
Saisuda Noojarern ◽  
Chulaluck Kuptanon ◽  
...  
Keyword(s):  
Gaucher Disease ◽  
Age Of Onset ◽  
Lysosomal Storage ◽  
Pathogenic Variants ◽  
Medical Centers ◽  
Neurologic Involvement ◽  
Therapeutic Research ◽  
Type 3

Abstract Background Gaucher disease (GD is a rare lysosomal storage disorder, characterized by hepatosplenomegaly and pancytopenia, with or without neurologic involvement. The disorder is categorized into three phenotypes: GD type 1 or nonneuronopathic GD; GD type 2 or acute neuronopathic GD; and GD type 3 or chronic neuronopathic GD. The purposes of this study were to describe clinical characteristics of Thai GD in patients diagnosed and/or followed up during 2010–2018 and to perform re-genotyping including analysis of GBA recombinant alleles which had not been investigated in Thai patients before. Results There were 27 patients from seven medical centers, enrolled in the study. All the cases had pediatric onset. GD3 (44.5%) was the most common phenotype, followed by GD2 (40.7%) and GD1 (14.8%), with one case of neonatal GD. The median age of onset for GD1, GD2, and GD3 was 72, 4 and 12 months, respectively, suggesting relatively earlier onset of GD1 and GD3 in Thai patients. All patients with GD1 and most patients with GD3 received ERT. Four patients with GD3 had ERT followed by HSCT. Patients with GD3 who received no or late ERT showed unfavorable outcomes. We identified 14 mutations including two novel (p.S384F and p.W533*) and 12 reported pathogenic variants: p.L483P, p.N409S, p.R159W, p.P305A, p.A175G, p.D448H, p.V414L, IVS2 + 1G > A, IVS6-1G > C, IVS7 + 1G > C, IVS9-3C > G, and Rec1a. The p.L483P was the most prevalent allele found in this study, at 66% (33/50 alleles), followed by IVS2 + 1G > A, Rec1a, and IVS6-1G > C. Twenty-four percent of patients were reassigned with validated genotypes, most of whom (4 of 6) were patients with GD2. The [p.S384F + p.W533*] being compounded with p.L483P, was found in the patient with neonatal GD, suggesting that the p.S384F could potentiate the deleterious effect of the p.W533*, and/or vice versa. Conclusions Neuronopathic GD was strikingly prevalent among Thai affected population. Homozygous p.L483P was the most common genotype identified in Thai patients. Recombinant allele Rec1a and splicing mutations were associated with GD2 and severe cases of GD3. Mutation spectrum could be useful for designing stepwise molecular analysis, genetic screenings in population, and new therapeutic research for neuronopathic GD.

scholarly journals Genotype/phenotype relationship in Gaucher disease patients. Novel mutation in glucocerebrosidase gene

2020 ◽  
Vol 0 (0) ◽  
Author(s):  
Esperanza Lepe-Balsalobre ◽  
José D. Santotoribio ◽  
Ramiro Nuñez-Vazquez ◽  
Salvador García-Morillo ◽  
Pilar Jiménez-Arriscado ◽  
...  
Keyword(s):  
Gaucher Disease ◽  
Novel Mutation ◽  
Clinical Manifestations ◽  
University Hospital ◽  
Neurological Involvement ◽  
Lysosomal Storage ◽  
Neurological Alterations ◽  
Form Type ◽  
Monitoring Treatment

AbstractObjectivesGaucher disease (GD) is the most common inherited lysosomal storage disease, caused by mutations in acid β-glucosidase (GBA) gene. This study aimed to identify mutations in Andalusia patients with GD and their genotype-phenotype correlation.MethodsDescriptive observational study. University Hospital Virgen del Rocio patients diagnosed from GD from 1999 to 2019 were included. Demographic and clinical data, β-glucocerebrosidase activity, variants pathogenic in GBA gene and biomarkers for monitoring treatment were collected from digital medical record.ResultsTwenty-six patients with aged between 1 day and 52 years were studied. A total of six mutations described as pathogenic and one mutation not described above [c.937T>C (p.Tyr313His)] were identified in the GBA gene, four patients were homozygotes and 22 compound heterozygotes. Twenty-four patients were diagnosed in non-neuropathic form (type 1) and two cases presented neurological involvement (type 2 or 3). The most common variant was c.1226A>G (p.Asn409Ser), which was detected in 24 patients, followed by c.1448T>C (p.Leu483Pro) variant, identified in 13 patients. The c.1448T>C (p.Leu483Pro) mutation has been presented in the most severe phenotypes with neurological involvement associated with type 2 and 3 GD, while c.1226A>G (p.Asn409Ser) mutation has not been associated with neurological alterations. Splenomegaly and bone disease were the most frequent clinical manifestations, and thrombocytopenia was the most common hematological disorder.ConclusionsThe c.1226A>G (p.Asn409Ser) and c.1448T>C (p.Leu483Pro) mutations were the most common. The c.937T>C (p.Tyr313His) was identified as a novel mutation. The c.1448T>C (p.Leu483Pro) mutation was associated with neurological alterations and c.1226A>G (p.Asn409Ser) mutation has not been associated it.

scholarly journals Coxarthritis as the Presenting Symptom of Gaucher Disease Type 1

Arthritis ◽  
2011 ◽  
Vol 2011 ◽  
pp. 1-4 ◽  
Author(s):  
Giacomo Brisca ◽  
Maja Di Rocco ◽  
Paolo Picco ◽  
Maria Beatrice Damasio ◽  
Alberto Martini
Keyword(s):  
Gaucher Disease ◽  
Lysosomal Storage Disorder ◽  
Signs And Symptoms ◽  
Mononuclear Phagocyte ◽  
Disease Type ◽  
Lysosomal Storage ◽  
Skeletal Disease ◽  
Abnormal Accumulation ◽  
Gaucher Disease Type 1

Gaucher disease (GD) type 1 is the most common lysosomal storage disorder due to beta glucocerebrosidase deficiency leading to an abnormal accumulation of its substrate, glucocerebroside, in the mononuclear phagocyte system. The disease presentation is usually characterized by signs and symptoms related to hypersplenism, such as splenomegaly, anaemia, thrombocytopenia and leucopenia. Skeletal disease may occur later for the infiltration of bone marrow by macrophages infiltration and bone resorption: bone involvement may be heterogeneously manifested by symptoms ranging from bone crisis to avascular necrosis, osteoporosis and defect in remodeling of long bones. Herein, we report a patient in whom the osteoarticular involvement has been the only symptom of the disease stressing that this unusual presentation of GD has prompted a wide differential diagnosis with more common forms of coxitis.

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