Prevalence of glucocerebrosidase mutations in the Israeli Ashkenazi Jewish population

Horowitz, Mia; Pasmanik‐Chor, Metsada; Borochowitz, Zvi; Falik‐Zaccai, Tzipora C.; Heldmann, Keren; Carmi, Rivka; Parvari, Ruth; Beit-Or, Hannah; Goldman, Boleslav; Peleg, Leah; Levy-Lahad, Ephrat; Renbaum, Paul; Legum, Searl; Shomrat, Ruth; Yeger, Hannah; Benbenisti, Dalit; Navon, Ruth; Dror, Vardit; Shohat, Mordechai; Magal, Nurit; Navot, N.; Eyal, Nurit

doi:10.1002/(sici)1098-1004(1998)12:4<240::aid-humu4>3.0.co;2-j

Cited by 93 publications

(71 citation statements)

References 9 publications

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“…N370S, the most common mutant allele in Jewish and non-Jewish patient populations [12,13] and known to be always associated with type 1 GD [14], was not detected in our Korean patients. The L444P mutation was the most frequent mutation, seen in 20.8% of our patients, followed by G46E (13.9%), F213I (12.5%), and R257Q (9.7%).…”

Section: Resultsmentioning

confidence: 58%

“…Indeed, 5 patients had homozygous mutations of these 4 alleles; 2 patients with L444P/L444P and 1 patient each with G46E/G46E, F213I/F213I, or R257Q/R257Q. Several reports have suggested that L444P compound heterozygous mutations are associated with type 2 GD (severe type) and that the L444P/L444P homozygous mutation is more frequently associated with type 3 GD than with types 1 and 2 [10,[12][13][14][15][16]. In Korean GD patients, the L444P/L444P mutation was detected in 2 patients (cases No.…”

Section: Resultsmentioning

confidence: 99%

“…Diagnosis was based on standard diagnostic Blood Cells, Molecules, and Diseases 46 (2011) [11][12][13][14] criteria [1][2][3], and included a glucocerebrosidase enzyme activity test employing fluorescence-activated cell sorter analysis. Patients were clinically categorized into 3 major phenotypic subtypes based on age of onset and symptoms related to central nervous system involvement, as follows: 14 patients were type 1, nonneuronopathic; 8 were type 2, acute neuronopathic; and 14 were type 3, subacute neuronopathic.…”

Section: Subjectsmentioning

confidence: 99%

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Clinical and genetic characteristics of Korean patients with Gaucher disease

Jeong

Park²,

Kim

2011

Blood Cells, Molecules, and Diseases

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Section: Resultsmentioning

confidence: 58%

Section: Resultsmentioning

confidence: 99%

Section: Subjectsmentioning

confidence: 99%

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Clinical and genetic characteristics of Korean patients with Gaucher disease

Jeong

Park²,

Kim

2011

Blood Cells, Molecules, and Diseases

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“…Although Ͼ200 different mutations in GlcCerase have been reported, the N370S and L444P missense mutations represent the most prevalent ones in the Western hemisphere, with the former found in 70% of Ashkenazi Jews with the disease (3)(4)(5)(6). The N370S mutation is associated with type 1 disease, and it results in an enzyme with lower catalytic activity (3-16% of wild type) and impaired exit from the endoplasmic reticulum (ER) (7)(8)(9).…”

mentioning

confidence: 99%

The iminosugar isofagomine increases the activity of N370S mutant acid β-glucosidase in Gaucher fibroblasts by several mechanisms

Steet

Chung

Wustman

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

202

233

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Gaucher disease is a lysosomal storage disorder caused by deficiency in lysosomal acid ␤-glucosidase (GlcCerase), the enzyme responsible for the catabolism of glucosylceramide. One of the most prevalent disease-causing mutations, N370S, results in an enzyme with lower catalytic activity and impaired exit from the endoplasmic reticulum. Here, we report that the iminosugar isofagomine (IFG), an active-site inhibitor, increases GlcCerase activity 3.0 ؎ 0.6-fold in N370S fibroblasts by several mechanisms. A major effect of IFG is to facilitate the folding and transport of newly synthesized GlcCerase in the endoplasmic reticulum, thereby increasing the lysosomal pool of the enzyme. In addition, N370S GlcCerase synthesized in the presence of IFG exhibits a shift in pH optimum from 6.4 to 5.2 and altered sensitivity to SDS. Although IFG fully inhibits GlcCerase in the lysosome in an in situ assay, washout of the drug leads to partial recovery of GlcCerase activity within 4 h and full recovery by 24 h. These findings provide support for the possible use of active-site inhibitors in the treatment of some forms of Gaucher disease.

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“…15,[25][26][27][28] Nearly 300 mutations have been identified, including frameshift mutations, point mutations, deletions, insertions and splice site mutations. 29 Four mutations N370S (c.1226A>G), L444P (C.1448T>C), 84GG (-c.84dupG) and IVS2+1 (c.27+1G>A) account for approximately 90 % of the disease causing alleles in the Ashkenazi Jewish population.…”

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confidence: 99%

A Rare Condition in Haematological Practice – Gaucher Disease

Cappellini

2015

European Oncology &Amp; Haematology

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Gaucher disease, which is caused by an inherited glucocerebrosidase deficiency, is the most prevalent lysosomal storage disease worldwide. Estimated prevalence of Gaucher disease is 1:50,000 in most countries and the disease has its highest incidence in the Ashkenazi Jewish population. Type 1 (non-neuropathic) Gaucher disease is by far the most common form. Gaucher disease type 1 should be considered in cases of unexplained splenomegaly with or without bleeding diathesis, skeletal manifestations or hepatomegaly. Diagnosis is made by demonstrating decreased glucocerebrosidase activity in peripheral blood leucocytes. Dried blood spots can be used for screening but conventional enzyme assay on heparinised blood is essential. Patients with Gaucher disease may have extensive organ involvement despite relatively minor overt symptomatology. Evidence suggests that Gaucher disease may remain undiagnosed for years, leading to severe complications that are preventable or reversible with enzyme replacement therapy. These complications include avascular necrosis, severe bleeding, chronic bone pain, pathological fractures, growth failure, liver pathology and life-threatening sepsis. Most patients with Gaucher disease are initially evaluated by a haematologist–oncologist. Improved education is needed to enable prompt detection of Gaucher disease. An increased risk of multiple myeloma and haematological and non-haematological malignancies has been reported in type 1 Gaucher disease. This review aims to offer familiarisation with a rare disorder in haematological practice, focusing on adult patient management.

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Prevalence of glucocerebrosidase mutations in the Israeli Ashkenazi Jewish population

Cited by 93 publications

References 9 publications

Clinical and genetic characteristics of Korean patients with Gaucher disease

Clinical and genetic characteristics of Korean patients with Gaucher disease

The iminosugar isofagomine increases the activity of N370S mutant acid β-glucosidase in Gaucher fibroblasts by several mechanisms

A Rare Condition in Haematological Practice – Gaucher Disease

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