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Titolo:
PARTIAL DUPLICATION OF THE EGF PRECURSOR HOMOLOGY DOMAIN OF THE LDL-RECEPTOR PROTEIN CAUSING FAMILIAL HYPERCHOLESTEROLEMIA (FH-SALERNO)
Autore:
BERTOLINI S; PATEL DD; COVIELLO DA; LELLI N; GHISELLINI M; TIOZZO R; MASTURZO P; ELICIO N; KNIGHT BL; CALANDRA S;
Indirizzi:
UNIV MODENA,INST GEN PATHOL I-41100 MODENA ITALY UNIV MODENA,INST GEN PATHOL I-41100 MODENA ITALY UNIV GENOA,CTR ATHEROSCLEROSIS PREVENT,DEPT INTERNAL MED GENOA ITALY UNIV GENOA,INST BIOL & GENET GENOA ITALY HAMMERSMITH HOSP,MRC,LIPOPROTEIN TEAM LONDON ENGLAND
Titolo Testata:
Journal of lipid research
fascicolo: 8, volume: 35, anno: 1994,
pagine: 1422 - 1430
SICI:
0022-2275(1994)35:8<1422:PDOTEP>2.0.ZU;2-V
Fonte:
ISI
Lingua:
ENG
Soggetto:
LOW-DENSITY-LIPOPROTEIN; GENE; EXONS; SUBJECT; RNA;
Keywords:
FAMILIAL HYPERCHOLESTEROLEMIA; LDL-RECEPTOR GENE; EXON DUPLICATION; LIGAND BLOTTING; IMMUNOBLOTTING; RECEPTOR SYNTHESIS AND DEGRADATION;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Science Citation Index Expanded
Citazioni:
23
Recensione:
Indirizzi per estratti:
Citazione:
S. Bertolini et al., "PARTIAL DUPLICATION OF THE EGF PRECURSOR HOMOLOGY DOMAIN OF THE LDL-RECEPTOR PROTEIN CAUSING FAMILIAL HYPERCHOLESTEROLEMIA (FH-SALERNO)", Journal of lipid research, 35(8), 1994, pp. 1422-1430

Abstract

A novel mutation of low density lipoprotein (LDL)-receptor gene was found in an Italian familial hypercholesterolemia (FH) patient during ascreening of 300 FH patients. The proband as well as her daughter were found to be heterozygotes for the mutation. Binding, internalization, and degradation of I-125-labeled LDL by the proband's fibroblasts were reduced to approximately 50% compared to values found in control cells. DNA analysis by Southern blotting showed that the mutant allele was characterized by an insertion of about 10 kb, which resulted from aduplication of exons 9-14 of the LDL-receptor gene. In addition, Northern blot analysis of the proband's RNA showed, besides the normal-sized LDL-receptor mRNA (5.3 kb), an additional mRNA of about 6.2 kb. Thejunction between exon 14 and the duplicated exon 9 was amplified by polymerase chain reaction (PCR) from the cDNA. The sequence of the amplified fragment showed that exon 14 joined the duplicated exon 9 without changing the reading frame. The derived amino acid sequence indicated that the mutated receptor protein had a partial duplication of the EGF precursor homology domain. Ligand and immunoblotting revealed that proband's fibroblasts contained one-half of the normal amount of LDL-receptor protein (molecular mass 130 kDa) and an abnormally large receptor of approximately 160 kDa. The amount of this abnormal receptor as detected by two monoclonal antibodies (10A2 and 4B3) was found to be approximately 30% that of the normal LDL-receptor present in the same cells. Treatment of the proband's cells with pronase greatly reduced the amount of both normal and abnormal receptors detected, indicating that both receptors were present on the cell surface. Pulse-chase experiments using [S-35]methionine indicated that the receptor was processedto the mature form (195 kDa), although at a rate slightly slower thanthe normal receptor (160 kDa) present in the same cells. However, themature abnormal receptor was degraded much more rapidly (half life 4.6 h) than the normal receptor present in the proband's cells (half life 11.9 h) or in normal cells (half life 12.4 h). jlr In conclusion, the mutant allele present in our proband produces an abnormally large receptor protein that is normally processed to the mature form but is degraded more rapidly than the normal counterpart. As the proband's family originated from the city of Salerno, in southern Italy, the mutation was named FHSalerno.

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Documento generato il 04/12/20 alle ore 16:13:18