Gaucher disease is the most common glycolipid storage disorder. Its prevalence is highest in the Jewish population where the birth incidence has been estimated to be over 1:500. Cloning and sequencing of the gene for glucocerebrosidase, the enzyme that is deficient in Gaucher disease, has revealed a variety of mutations. The two most common of these, located at nt 1226 and nt 1448, account for approximately 75% of the Gaucher disease alleles both in the Jewish and non-Jewish population. A relationship exists between the genotype of patients and the Gaucher disease phenotype that they express, but there are many exceptions to the disease pattern prototype. The following studies are proposed: 1) DNA from a large number of patients with Gaucher disease will be studied to detect known mutations and then to identify new mutations. At least one of the more common unidentified mutations appears to be regulatory; 2) The glucocerebrosidase gene complex will be studied to identify additional polymorphisms that can be useful in genetic counseling in families in which the precise mutation is unknown. Such studies will also allow rough computation of how recently the common Jewish Gaucher disease mutation has arisen; 3) Attempts will be made to explain deviations of the phenotype that is expressed by patients from that which is usual for any given genotype. For example, patients homozygous for the common Jewish mutation at nt 1226 usually have mild disease, but may have absolutely no disease manifestation or may have moderately severe disease. These studies will involve searching for additional mutations, for deletions that produce spurious genotypes and investigations of the expression of saposin C in cultured cells; 4) A study of the uptake of mannose terminated glucocerebrosidase (Ceredase ) into murine macrophage lines, murine resident macrophages, human resident pulmonary macrophages, and human cultured monocyte/macrophages will be carried out. These studies will include measurements of numbers of mannose receptors, their affinity for the enzyme, the rate of internalization, the rate of receptor generation, and the rate of degradation of enzyme in the cell. Such studies will provide a rational basis for the design of dose schedules for treatment of patients with Ceredase, a very costly, but effective treatment for Gaucher disease.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
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Medical Biochemistry Study Section (MEDB)
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Scripps Research Institute
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Beutler, E; Gelbart, T (1996) Glucocerebrosidase (Gaucher disease). Hum Mutat 8:207-13
Beutler, E; Baronciani, L (1996) Mutations in pyruvate kinase. Hum Mutat 7:1-6
Beutler, E; Gelbart, T; Balicki, D et al. (1996) Gaucher disease: four families with previously undescribed mutations. Proc Assoc Am Physicians 108:179-84
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Beutler, E; Kuhl, W; Vaughan, L M (1995) Failure of alglucerase infused into Gaucher disease patients to localize in marrow macrophages. Mol Med 1:320-4
Beutler, E; Demina, A; Laubscher, K et al. (1995) The clinical course of treated and untreated Gaucher disease. A study of 45 patients. Blood Cells Mol Dis 21:86-108
Beutler, E; Gelbart, T (1994) Two new Gaucher disease mutations. Hum Genet 93:209-10

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