title: A novel mutation of the apolipoprotein A-I gene in a family with familial combined hyperlipidemia.
abstract: We report a large family in which four members showed a plasma lipid profile consistent with the clinical diagnosis of familial combined hyperlipidemia (FCHL). One of these patients was found to have markedly reduced HDL cholesterol (HDL-C) (0.72 mmol/l) and Apo A-I (72 mg/dl) levels, a condition suggestive of the presence of a mutation in one of the HDL-related genes. The analysis of APOA1 gene revealed that this patient was heterozygous for a cytosine insertion in exon 3 (c.49-50 ins C), resulting in a frame-shift and premature stop codon at position 26 of pro-Apo A-I (Q17PFsX10). This novel mutation, which prevents the synthesis of Apo A-I, was also found in four family members, including three siblings and the daughter of the proband. Carriers of Apo A-I mutation had significantly lower HDL-C and Apo A-I than non-carriers family members (0.77+/-0.15 mmol/l vs. 1.15+/-0.20 mmol/l, P<0.005; 71.4+/-9.1mg/dl vs. 134.0+/-14.7 mg/dl, P<0.005, respectively). Two of the APOA1 mutation carriers, who were also heavy smokers, had fibrous plaques in the carotid arteries causing mild stenosis (20%). The intimal-media thickness in the two other adult carriers was within the normal range. The other non-carriers family members with FCHL had either overt vascular disease or carotid atherosclerosis at ultrasound examination. This observation suggests that the low HDL-C/low Apo A-I phenotype may result from a genetic defect directly affecting HDL metabolism, even in the context of a dyslipidemia which, like FCHL, is associated with low plasma HDL-C.
authors.affiliation: Department of Internal Medicine, University of Genoa, Viale Benedetto XV 6, I-16132 Genoa, Italy.
authors.forename: Livia
authors.initials: L
authors.lastname: Pisciotta
authors.forename: Tommaso
authors.initials: T
authors.lastname: Fasano
authors.forename: Laura
authors.initials: L
authors.lastname: Calabresi
authors.forename: Antonella
authors.initials: A
authors.lastname: Bellocchio
authors.forename: Raffaele
authors.initials: R
authors.lastname: Fresa
authors.forename: Claudia
authors.initials: C
authors.lastname: Borrini
authors.forename: Sebastiano
authors.initials: S
authors.lastname: Calandra
authors.forename: Stefano
authors.initials: S
authors.lastname: Bertolini
mesh_terms: D000328:Adult; D000368:Aged; D016632:Apolipoprotein A-I / Q000235:genetics*; D001055:Apolipoproteins B / Q000235:genetics; D002340:Carotid Artery Diseases / Q000000981:diagnostic imaging / Q000235:genetics / Q000473:pathology; D008076:Cholesterol, HDL / Q000097:blood / Q000172:deficiency; D018389:Codon, Nonsense; D004951:Esterification; D005192:Family Health; D005260:Female; D016368:Frameshift Mutation; D006801:Humans; D006950:Hyperlipidemia, Familial Combined / Q000235:genetics*; D008055:Lipids / Q000097:blood; D008297:Male; D008875:Middle Aged; D010375:Pedigree; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases; D011973:Receptors, LDL / Q000235:genetics; D012697:Serine Endopeptidases / Q000235:genetics; D012907:Smoking; D014463:Ultrasonography
chemical_list: D016632:Apolipoprotein A-I; D001055:Apolipoproteins B; D008076:Cholesterol, HDL; D018389:Codon, Nonsense; D008055:Lipids; D011973:Receptors, LDL; C472125:PCSK9 protein, human; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases; D012697:Serine Endopeptidases