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EnglishCholesteryl ester transfer protein (CETP) is a plasma glycoprotein that catalyses the transfer of cholesteryl esters from HDL to the other plasma lipoproteins. Genetic deficiency of CETP is one of the known causes of elevation of plasma HDL-C (primary hyperalphalipoproteinemia, HALP). We sequenced CETP gene in a group of 24 Italian subjects with primary HALP (HDL-C > 80 mg/dl) suspected to have CETP deficiency. Two unrelated subjects both coming from the same geographical district, were found to be heterozygous for a nucleotide substitution in exon 6 (c.544C > T) and another subject was found to be heterozygous for a C > T transition in exon 9 (c.802C > T). Both mutations introduce a premature stop codon and are predicted to cause the production of truncated proteins (Q165X and R268X, respectively) devoid of function. The fourth proband was found to carry a T > C substitution in intron 15 (c.1407 + 2T > C) predicted to abolish the function of the donor splice site. To define the effect of this mutation on CETP pre-mRNA splicing we analysed CETP mRNA in COS-1 cells expressing a CETP minigene harbouring the mutation. The analysis of minigene transcript in COS-1 cells showed that IVS15 + 2T > C mutation caused the formation of an abnormal mRNA in which exon 14 joins directly to exon 16, predicted to encode a truncated peptide of 435 amino acids. In mutation carriers plasma CETP activity was found to be reduced by 38-60%. These are the first mutations in the CETP gene found in Italian subjects with HALP. © 2008 Elsevier Ireland Ltd. All rights reserved.
| Data di pubblicazione: | 2009 | |
| Titolo: | Novel mutations of CETP gene in Italian subjects with hyeralphalipoproteinemia | |
| Autori: | Cefalù, Angelo B.; Noto, Davide; Magnolo, Lucia; Pinotti, Elisa; Gomaraschi, Monica; Martini, Scipione; Vigna, Giovanni Battista; Calabresi, Laura; Tarugi, Patrizia | |
| Rivista: | ATHEROSCLEROSIS | |
| Keywords: | CETP activity; CETP gene mutations; Familial hyperalphalipoproteinemia; HDL size; Adolescent; Adult; Aged; Animals; Biomarkers; COS Cells; Cercopithecus aethiops; Cholesterol Ester Transfer Proteins; Cholesterol, HDL; DNA Mutational Analysis; European Continental Ancestry Group; Female; Humans; Hyperlipoproteinemias; Italy; Male; Middle Aged; Phenotype; RNA, Messenger; Transfection; Up-Regulation; Young Adult; Mutation; Cardiology and Cardiovascular Medicine | |
| Abstract in inglese: | Cholesteryl ester transfer protein (CETP) is a plasma glycoprotein that catalyses the transfer of cholesteryl esters from HDL to the other plasma lipoproteins. Genetic deficiency of CETP is one of the known causes of elevation of plasma HDL-C (primary hyperalphalipoproteinemia, HALP). We sequenced CETP gene in a group of 24 Italian subjects with primary HALP (HDL-C > 80 mg/dl) suspected to have CETP deficiency. Two unrelated subjects both coming from the same geographical district, were found to be heterozygous for a nucleotide substitution in exon 6 (c.544C > T) and another subject was found to be heterozygous for a C > T transition in exon 9 (c.802C > T). Both mutations introduce a premature stop codon and are predicted to cause the production of truncated proteins (Q165X and R268X, respectively) devoid of function. The fourth proband was found to carry a T > C substitution in intron 15 (c.1407 + 2T > C) predicted to abolish the function of the donor splice site. To define the effect of this mutation on CETP pre-mRNA splicing we analysed CETP mRNA in COS-1 cells expressing a CETP minigene harbouring the mutation. The analysis of minigene transcript in COS-1 cells showed that IVS15 + 2T > C mutation caused the formation of an abnormal mRNA in which exon 14 joins directly to exon 16, predicted to encode a truncated peptide of 435 amino acids. In mutation carriers plasma CETP activity was found to be reduced by 38-60%. These are the first mutations in the CETP gene found in Italian subjects with HALP. © 2008 Elsevier Ireland Ltd. All rights reserved. | |
| Digital Object Identifier (DOI): | 10.1016/j.atherosclerosis.2008.08.031 | |
| Handle: | http://hdl.handle.net/11392/2353772 | |
| Appare nelle tipologie: | 03.1 Articolo su rivista |
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| File | Descrizione | Tipologia | Licenza | |
|---|---|---|---|---|
| 28 CETP mutations Atherosclerosis09.pdf | Articolo principale | Full text (versione editoriale) | NON PUBBLICO - Accesso privato/ristretto | Administrator Richiedi una copia |
| 28 supplementary Atherosclerosis.doc | Supplementary data | Altro materiale allegato | NON PUBBLICO - Accesso privato/ristretto | Administrator Richiedi una copia |
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