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Novel mutations of the PCSK9 gene cause variable phenotype of autosomal dominant hypercholesterolemia
Human mutation, 2005-11, Vol.26 (5), p.497-497
Allard, Delphine
Amsellem, Sabine
Abifadel, Marianne
Trillard, Mélanie
Devillers, Martine
Luc, Gérald
Krempf, Michel
Reznik, Yves
Girardet, Jean-Philippe
Fredenrich, Alexandre
Junien, Claudine
Varret, Mathilde
Boileau, Catherine
Benlian, Pascale
Rabès, Jean-Pierre
2005
Volltextzugriff (PDF)
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Autor(en) / Beteiligte
Allard, Delphine
Amsellem, Sabine
Abifadel, Marianne
Trillard, Mélanie
Devillers, Martine
Luc, Gérald
Krempf, Michel
Reznik, Yves
Girardet, Jean-Philippe
Fredenrich, Alexandre
Junien, Claudine
Varret, Mathilde
Boileau, Catherine
Benlian, Pascale
Rabès, Jean-Pierre
Titel
Novel mutations of the PCSK9 gene cause variable phenotype of autosomal dominant hypercholesterolemia
Ist Teil von
Human mutation, 2005-11, Vol.26 (5), p.497-497
Ort / Verlag
Hoboken: Wiley Subscription Services, Inc., A Wiley Company
Erscheinungsjahr
2005
Quelle
MEDLINE
Beschreibungen/Notizen
Autosomal dominant hypercholesterolemia (ADH) is a frequent (1/500) monogenic inherited disorder characterized by isolated elevation of LDL leading to premature cardiovascular disease. ADH is known to result from mutations at two main loci: LDLR (encoding the low density lipoprotein receptor), and APOB (encoding apolipoprotein B100), its natural ligand. We previously demonstrated that ADH is also caused by mutations of the PCSK9 (proprotein convertase subtilisin/kexin type 9) gene that encodes Narc‐1 (neural apoptosis‐regulated convertase 1). However, the role of this novel disease locus as a cause of hypercholesterolemia remains unclear. In the present study, we analysed the PCSK9 coding region and intronic junctions in 130 adult or pediatric patients with ADH, previously found as being non LDLR/non APOB mutation carriers. Four novel heterozygous missense variations were found: c.654A>T (p.R218S), c.1070G>A (p.R357H), c.1405C>T (p.R469W), and c.1327G>A (p.A443T). All mutations were absent in 340 normolipidemic controls. Except for the A443T, all mutations are nonconservative and modify a highly conserved residue. Segregation with hypercholesterolemia is incomplete in one pedigree. Type and severity of hyperlipidemia and of cardiovascular disease could vary among subjects from the same family. Finally, the proband carrying the R357H mutation exhibited very high plasma cholesterol during pregnancy, whereas the proband carrying the p.R469W mutation exhibited a severe phenotype of hypercholesterolemia in combination with a LDLR mutation resulting from a frameshift at residue F382 (1209delC). These observations suggest that variations in PCSK9 are a rare cause of non LDLR/non APOB ADH (∼ 2.3%) and that additional environmental or genetic factors may contribute to the phenotype caused by PCSK9 missense mutations in humans. © 2005 Wiley‐Liss, Inc.
Sprache
Englisch
Identifikatoren
ISSN: 1059-7794
eISSN: 1098-1004
DOI: 10.1002/humu.9383
Titel-ID: cdi_proquest_miscellaneous_68697596
Format
–
Schlagworte
Apolipoproteins
,
Apolipoproteins B - genetics
,
autosomal dominant hypercholesterolemia (ADH)
,
Cardiovascular disease
,
Cholesterol
,
DNA Mutational Analysis
,
Genes
,
Genetic testing
,
Genotype & phenotype
,
Humans
,
Hypercholesterolemia - diagnosis
,
Hypercholesterolemia - genetics
,
Ligands
,
Low density lipoprotein receptors
,
missense mutation
,
Mutation
,
Mutation, Missense
,
PCSK9
,
Pediatrics
,
Pedigree
,
Phenotype
,
Physical Chromosome Mapping
,
Plasma
,
Proprotein Convertase 9
,
Proprotein Convertases
,
Receptors, LDL - genetics
,
Serine Endopeptidases - genetics
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