title: A complex phenotype in a child with familial HDL deficiency due to a novel frameshift mutation in APOA1 gene (apoA-IGuastalla).
abstract: BACKGROUND
  We describe a kindred with high-density lipoprotein (HDL) deficiency due to APOA1 gene mutation in which comorbidities affected the phenotypic expression of the disorder.
  
  
  METHODS
  An overweight boy with hypertriglyceridemia (HTG) and HDL deficiency (HDL cholesterol 0.39 mmol/L, apoA-I 40 mg/dL) was investigated. We sequenced the candidate genes for HTG (LPL, APOC2, APOA5, GPIHBP1, LMF1) and HDL deficiency (LCAT, ABCA1 and APOA1), analyzed HDL subpopulations, measured cholesterol efflux capacity (CEC) of sera and constructed a model of the mutant apoA-I.
  
  
  RESULTS
  No mutations in HTG-related genes, ABCA1 and LCAT were found. APOA1 sequence showed that the proband, his mother and maternal grandfather were heterozygous of a novel frameshift mutation (c.546_547delGC), which generated a truncated protein (p.[L159Afs*20]) containing 177 amino acids with an abnormal C-terminal tail of 19 amino acids. Trace amounts of this protein were detectable in plasma. Mutation carriers had reduced levels of LpA-I, preβ-HDL and large HDL and no detectable HDL-2 in their plasma; their sera had a reduced CEC specifically the ABCA1-mediated CEC. Metabolic syndrome in the proband explains the extremely low HDL cholesterol level (0.31 mmol/L), which was half of that found in the other carriers. The proband's mother and grandfather, both presenting low plasma low-density lipoprotein cholesterol, were carriers of the β-thalassemic trait, a condition known to be associated with a reduced low-density lipoprotein cholesterol and a reduced prevalence of cardiovascular disease. This trait might have delayed the development of atherosclerosis related to HDL deficiency.
  
  
  CONCLUSIONS
  In these heterozygotes for apoA-I truncation, the metabolic syndrome has deleterious effect on HDL system, whereas β-thalassemia trait may delay the onset of cardiovascular disease.
authors.affiliation: Department of Internal Medicine, University of Genoa, Genoa, Italy.
authors.forename: Livia
authors.initials: L
authors.lastname: Pisciotta
authors.affiliation: Center E. Grossi Paoletti, Department of Pharmacological and Biomolecular Sciences, University of Milan, Milan, Italy.
authors.forename: Cecilia
authors.initials: C
authors.lastname: Vitali
authors.affiliation: Department of Pharmacy, University of Parma, Parma, Italy.
authors.forename: Elda
authors.initials: E
authors.lastname: Favari
authors.affiliation: Department of Pharmacy, University of Genoa, Genoa, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Fossa
authors.affiliation: Department of Pharmacy, University of Parma, Parma, Italy.
authors.forename: Maria Pia
authors.initials: MP
authors.lastname: Adorni
authors.affiliation: Laboratory of Human Genetics, Galliera Hospital, Genoa, Italy.
authors.forename: Daniela
authors.initials: D
authors.lastname: Leone
authors.affiliation: Department of Internal Medicine, University of Genoa, Genoa, Italy.
authors.forename: Nathan
authors.initials: N
authors.lastname: Artom
authors.affiliation: Department of Internal Medicine, University of Genoa, Genoa, Italy.
authors.forename: Raffaele
authors.initials: R
authors.lastname: Fresa
authors.affiliation: Center E. Grossi Paoletti, Department of Pharmacological and Biomolecular Sciences, University of Milan, Milan, Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: Calabresi
authors.affiliation: Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, Modena, Italy. Electronic address: sebcal@unimore.it.
authors.forename: Sebastiano
authors.initials: S
authors.lastname: Calandra
authors.affiliation: Department of Internal Medicine, University of Genoa, Genoa, Italy. Electronic address: stefbert@unige.it.
authors.forename: Stefano
authors.initials: S
authors.lastname: Bertolini
mesh_terms: D000293:Adolescent; D000368:Aged; D000369:Aged, 80 and over; D001054:Apolipoproteins A / Q000097:blood / Q000235:genetics*; D001692:Biological Transport; D002784:Cholesterol / Q000097:blood / Q000378:metabolism; D005260:Female; D016368:Frameshift Mutation; D006801:Humans; D052456:Hypoalphalipoproteinemias / Q000097:blood / Q000235:genetics* / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D010375:Pedigree; D010641:Phenotype; D014280:Triglycerides / Q000097:blood / Q000235:genetics
chemical_list: D001054:Apolipoproteins A; D014280:Triglycerides; D002784:Cholesterol
keywords: APOA1 mutation; Hypertriglyceridemia; Metabolic syndrome; Truncated apoA-I; β-thalassemia trait