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Titolo:
ANALYSIS OF 2 DUPLICATIONS OF THE LDL RECEPTOR GENE AFFECTING INTRACELLULAR-TRANSPORT, CATABOLISM, AND SURFACE BINDING OF THE LDL RECEPTOR
Autore:
PATEL DD; LELLI N; GARUTI R; VOLTI SL; BERTOLINI S; KNIGHT BL; CALANDRA S;
Indirizzi:
UNIV MODENA,DIPARTIMENTO SCI BIOMED I-41100 MODENA ITALY UNIV MODENA,DIPARTIMENTO SCI BIOMED I-41100 MODENA ITALY HAMMERSMITH HOSP,CTR CLIN SCI,MRC,LIPOPROT TEAM LONDON ENGLAND UNIV CATANIA,PEDIAT CLIN CATANIA ITALY UNIV GENOA,CTR PREVENZ ARTERIOSCLEROSI,DIPARTIMENTO MED INTERNA GENOAITALY
Titolo Testata:
Journal of lipid research
fascicolo: 7, volume: 39, anno: 1998,
pagine: 1466 - 1475
SICI:
0022-2275(1998)39:7<1466:AO2DOT>2.0.ZU;2-W
Fonte:
ISI
Lingua:
ENG
Soggetto:
LOW-DENSITY-LIPOPROTEIN; MONOCYTE-DERIVED MACROPHAGES; FAMILIAL HYPERCHOLESTEROLEMIA; HUMAN FIBROBLASTS; ITALIAN PATIENTS; DELETIONS; MUTATIONS; SUBJECT; DEGRADATION; PRECURSOR;
Keywords:
FAMILIAL HYPERCHOLESTEROLEMIA; AMINO ACID SEQUENCE;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Science Citation Index Expanded
Citazioni:
25
Recensione:
Indirizzi per estratti:
Citazione:
D.D. Patel et al., "ANALYSIS OF 2 DUPLICATIONS OF THE LDL RECEPTOR GENE AFFECTING INTRACELLULAR-TRANSPORT, CATABOLISM, AND SURFACE BINDING OF THE LDL RECEPTOR", Journal of lipid research, 39(7), 1998, pp. 1466-1475

Abstract

Two novel mutations of the lo tv density lipoprotein (LDL)-receptor gene were found in two Italian familial hypercholesterolemia (FH)-heterozygotes. The first mutation was an 18 nucleotide duplication in exon 8 which is preceded by an A-->T transversion, The translation product of the mutant allele tvas predicted to be a receptor with an in-frame insertion of 6 amino acids in repeat B of the epidermal growth factor precursor homology domain. Analysis of LDL-receptor activity in the proband's fibroblasts showed a 50% reduction of I-125-labeled LDL binding and pulse-chase studies suggested that Little, if an); of the mutantprotein was processed to the mature form. The second mutation was a 7kb duplication (from intron 2 to intron 6) of exons 3 through 6, predicted to encode an elongated receptor with the duplication of repeats 2-7 of the ligand binding domain. The elongated receptor was processedslightly more slowly than the normal receptor, but was converted to amature form of the expected size. This mature, mutant receptor was degraded more rapidly than the normal receptor, On ligand blotting the elongated receptor bound twice as much LDL or beta-very low density lipoproteiu (beta VLDL) as the normal receptor. In contrast, maximum binding of LDL to proband's cells was decreased to approximately 70% of the normal cells with a significant increase in apparent affinity. Cell association at 37 degrees C, internalization, and degradation showed asimilar reduced maximum. Thus these mutations demonstrate that duplications of amino acid sequences in the low density lipoprotein LDL-receptor may disrupt the LDL-receptor pathway at different levels.

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Documento generato il 04/12/20 alle ore 22:23:02