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Titolo:
ASSOCIATION OF AN EXON-3 MUTATION (TRP66-]GLY) OF THE LDL RECEPTOR WITH VARIABLE EXPRESSION OF FAMILIAL HYPERCHOLESTEROLEMIA IN A FRENCH-CANADIAN FAMILY
Autore:
LEVY E; MINNICH A; CACAN SL; THIBAULT L; GIROUX LM; DAVIGNON J; LAMBERT M;
Indirizzi:
UNIV MONTREAL,HOP ST JUSTINE,DEPT NUTR MONTREAL PQ H3T 1C5 CANADA UNIV MONTREAL,HOP ST JUSTINE,DEPT PEDIAT MONTREAL PQ H3T 1C5 CANADA UNIV MONTREAL,CLIN RES INST MONTREAL,HYPERLIPIDEMIA & ATHEROSCLEROSISRES GRP MONTREAL PQ H3T 1C5 CANADA
Titolo Testata:
Biochemical and molecular medicine
fascicolo: 1, volume: 60, anno: 1997,
pagine: 59 - 69
SICI:
1077-3150(1997)60:1<59:AOAEM(>2.0.ZU;2-B
Fonte:
ISI
Lingua:
ENG
Soggetto:
LOW-DENSITY-LIPOPROTEIN; APOLIPOPROTEIN-E POLYMORPHISM; LIPASE GENE; DEFECTIVE APOLIPOPROTEIN-B-100; DEFICIENCY; DELETION; METABOLISM; DISEASE; PROTEINS; LIPIDS;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Science Citation Index Expanded
Science Citation Index Expanded
Citazioni:
43
Recensione:
Indirizzi per estratti:
Citazione:
E. Levy et al., "ASSOCIATION OF AN EXON-3 MUTATION (TRP66-]GLY) OF THE LDL RECEPTOR WITH VARIABLE EXPRESSION OF FAMILIAL HYPERCHOLESTEROLEMIA IN A FRENCH-CANADIAN FAMILY", Biochemical and molecular medicine, 60(1), 1997, pp. 59-69

Abstract

The ligand-binding domain of low-density lipoprotein (LDL) is composed of seven 40-amino-acid repeats encoded by exons 2-6. Previous studies identified a missense mutation in codon 66 of exon 3, which resultedin the production of LDL receptor protein that is not processed to its mature form. In the current investigation, we documented the presence of two identical mutant LDL receptor alleles (Trp(66) --> Gly) in two familial hypercholesterolemia (FH) probands, II-1 and II-2, associated with markedly elevated plasma LDL cholesterol (17.22 +/- 0.78 and 11.95 +/- 0.24 mmol/liter, respectively). Functional assays of their fibroblast LDL receptor showed inefficient binding (39 and 50%), internalization (33 and 37%), and degradation (32 and 37%) compared with controls. The contribution of the apo B gene to variation in LDL levels was virtually eliminated given the normal ligand interaction with cell surface receptors and the absence of the mutation occurring in codon 3500 of the apo B gene. Similarly, the homozygous apo E(3)/E(3) wildtypephenotype excluded any genetic contribution of apo E to the lipoprotein abnormalities. Furthermore, the LPL mutations commonly observed in French Canadians could not account for the observed lipid alterations. Several alterations in lipoprotein composition characterized VLDL, IDL, LDL, HDL(2), and HDL(3) fractions. Moreover, defective intestinal fat transport was observed in both probands (II-1 and II-2). Thus, the disturbance of lipoprotein concentration, composition, size, and metabolism may in part be related to the exon 3 mutation (Trp(66) --> Gly) of the LDL receptor gene. The biochemical phenotype was more severe inthe father (I-1) than in the mother (I-2), and in the younger homozygous proband (II-1) than in the older (II-2). The greater severity was associated with a higher LDL cholesterol/HDL cholesterol ratio. Whether the differences between the two probands are due to polygenic factors or to a metabolic consequence of a major nonallelic trait is unknown. Nevertheless, the present biochemical findings stress the extent of the lipid abnormalities associated with homozygous FH and the importance of the phenotypic variability encountered even among subjects carrying the same mutation. (C) 1997 Academic Press.

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Documento generato il 28/11/20 alle ore 18:37:05