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5. PREVALENCE OF ANGPTL3 AND APOB GENE MUTATIONS IN SUBJECTS WITH COMBINED HYPOLIPIDEMIA

Author

SPINA, Rossella, CEFALU', Angelo Baldassare, NOTO, Davide, VALENTI, Vincenza, FAYER, Francesca, DITTA, Mariangela, AVERNA, Maurizio, Pinotti E, Vigna G, Yue P, Schonfeld G, Kathiresan S, Tarugi P, Spina R, Cefalù AB, Noto D, Valenti V, Fayer, F, Pinotti E, Ditta M, Vigna G, Yue P, Schonfeld G, Kathiresan S, Tarugi P, and Averna M

Subjects
Settore MED/09 - Medicina Interna, ANGPTL3
Abstract

Introduction. Mutations of the ANGPTL3 gene have been found responsible for a novel form of primary hypobetalipoproteinemia (pHBL), the combined hypolipidemia, characterized by low total cholesterol (TC) and low HDL-cholesterol (HDL-C) levels. The aim of this work is to define the role of ANGPTL3 gene as determinant of the combined hypolipidemia phenotype in two large cohorts of 913 American and Italian subjects with primary hypobetalipoproteinemia (TC

Published
2011

7. Linkage of a Gene for Familial Hypobetalipoproteinemia to Chromosome 3p21.1-22

Author

Yuan, B., Neuman, R., Duan, S. H., Weber, J. L., Kwok, P. Y., Saccone, N. L., Wu, J. S., Liu, K.-Y., and Schonfeld, G.

Subjects
Human genetics -- Research, Familial diseases -- Causes of, Lipid metabolism -- Research, Apolipoproteins -- Research, Lipoproteins -- Research, Cholesterol -- Research, Gene mutations -- Research, Chromosomes -- Research, Biological sciences
Published
2000

47. Molecular bases of low production rates of apolipoprotein B-100 and truncated apoB-82 in a mutant HepG2 cell line generated by targeted modification of the apolipoprotein B gene.

Author

Srivastava, R A, Srivastava, N, Averna, M, Cefalu, A B, and Schonfeld, G

Abstract

In subjects with familial hypobetalipoproteinemia heterozygous for truncated forms of apolipoprotein B, both apoB-100 and the truncated forms are produced at lower than expected rates. We studied the mechanism of low levels of apoB in a cell model produced by targeted modification of the apob gene of HepG2 cells. One of the three alleles of apob was found to be targeted. The targeted cells expressed apoB-100 and B-82. The media of mutant cells contained 56% of the levels of apoB-100 present in the media of wild-type (WT) HepG2 cells. ApoB-82 was present at 11% of the apoB-100 levels in mutant cell media. An 85-kD protein (apoB-15) representing the N-terminal fragment of apoB was also secreted, but only in the mutant cell media. We examined the mechanism of low levels of apoB-82. Cellular apoB-82 mRNA was 11% of apoB-100 mRNA, lower than the 33% expected, but consistent with relative levels of apoB-82 in the media. ApoB mRNA transcription in WT and the mutant cells did not differ, while the levels of apoB-82 mRNA in nuclei and polysomes were 46% and 12% of the levels of apoB-100 mRNA, respectively, suggesting that the lower levels of apoB-82 mRNA were due to altered message stability. In a pulse/chase experiment with [35S] methionine, at zero time of chase, the amounts of apoB-100 in mutant cells was 66% that of WT levels, consistent with the modification of one allele. The fractions of newly synthesized apoB-100 secreted into the media at 2 h were 10% in the mutant cells and 19% in the WT cells, suggesting greater presecretory degradation of apoB-100 in the mutant cells. Thus, low levels of mutant apoB-82 mRNA gave rise to the low levels of apoB-82, while low levels of apoB-100 were due to low rates of secretion.

Published
1999

48. Known mutations of apoB account for only a small minority of hypobetalipoproteinemia.

Author

Wu, J, Kim, J, Li, Q, Kwok, P Y, Cole, T G, Cefalu, B, Averna, M, and Schonfeld, G

Abstract

Low LDL cholesterol and apoB levels in plasma cosegregate with mutations of apoB in some kindreds with familial hypobetalipoproteinemia. Approximately 35 apoB mutations, many specifying apoB truncations, have been described. Based on the centile nomenclature where the full-length nature apoB consisting of 4536 amino acids is designated as apoB-100, only those truncations of apoB >25% of normal length are detectable in plasma. Previously, we reported on five unrelated kindreds with familial hypobetalipoproteinemia in whom although no apoB truncations were detectable in plasma, low apoB levels were nevertheless linked to the apoB gene. In one of those kindreds, we reported a donor splice site mutation in intron 5 (specifying apoB- 4). We now describe a nonsense mutation in exon 10 (apoB-9) in two of the other unrelated families. Both the apoB-4 and apoB-9 mutations have been reported by others in unrelated families. Recurrent mutations of apoB-40 and apoB-55 also have been reported, suggesting that recurrent mutations of apoB may account for an appreciable proportion of familial hypobetalipoproteinemia kindreds. To test this hypothesis, we searched for four apoB mutations whose products are not detected in plasma including the apoB-4, apoB-9, and two other previously reported mutations in exons 21 and 25. We studied three groups with plasma cholesterols <130 mg/dl in whom no apoB truncations were detected in plasma: a) 28 FHBL probands from St. Louis, b) 151 individual St. Louisians, and c) 28 individual Sicilians. One subject from the 28 kindreds and two subjects among 151 hypobeta individuals from St. Louis harbored the exon 10 mutation. None of the other mutations were detected. Thus, among hypobeta lipoproteinemic subjects without any detectable apoB truncations in plasma, <5% had an apoB truncation-producing mutation. As only about 0.5% of hypobeta lipoproteinemic subjects have plasma-detectable apoB truncations, our data suggest that the known apoB truncations account for only a small proportion of hypocholesterolemia.

Published
1999

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