title: Characterization of three kindreds with familial combined hypolipidemia caused by loss-of-function mutations of ANGPTL3.
abstract: BACKGROUND
  Angiopoietin-like protein 3 (ANGPTL3) affects lipid metabolism by inhibiting the activity of lipoprotein and endothelial lipases. Angptl3 knockout mice have marked hypolipidemia, and heterozygous carriers of ANGPLT3, loss-of-function mutations were found among individuals in the lowest quartile of plasma triglycerides in population studies. Recently, 4 related individuals with primary hypolipidemia were found to be compound heterozygotes for ANGPTL3 loss-of-function mutations.
  
  
  RESULTS
  We resequenced ANGPTL3 in 4 members of 3 kindreds originally identified for very low levels of low-density lipoprotein cholesterol and high-density lipoprotein cholesterol (0.97±0.16 and 0.56±0.20 mmol/L, respectively) in whom no mutations of known candidate genes for monogenic hypobetalipoproteinemia and hypoalphalipoproteinemia had been detected. These subjects were found to be homozygous or compound heterozygous for ANGPTL3 loss-of-function mutations (p.G400VfsX5, p.I19LfsX22/p.N147X) associated with the absence of ANGPTL3 in plasma. They had reduced plasma levels of triglyceride-containing lipoproteins and of HDL particles that contained only apolipoprotein A-I and pre-β-high-density lipoprotein. In addition, their apolipoprotein B-depleted sera had a reduced capacity to promote cell cholesterol efflux through the various pathways (ABCA1-, SR-BI-, and ABCG1-mediated efflux); however, these subjects had no clinical evidence of accelerated atherosclerosis. Heterozygous carriers of the ANGPTL3 mutations had low plasma ANGPTL3 and moderately reduced low-density lipoprotein cholesterol (2.52±0.38 mmol/L) but normal plasma high-density lipoprotein cholesterol.
  
  
  CONCLUSIONS
  Complete ANGPTL3 deficiency caused by loss-of-function mutations of ANGPTL3 is associated with a recessive hypolipidemia characterized by a reduction of apolipoprotein B and apolipoprotein A-I-containing lipoproteins, changes in subclasses of high-density lipoprotein, and reduced cholesterol efflux potential of serum. Partial ANGPTL3 deficiency is associated only with a moderate reduction of low-density lipoprotein.
authors: Department of Internal Medicine, University of Genoa, Viale Benedetto XV 6, Genoa, Italy.
authors: Livia
authors: L
authors: Pisciotta
authors: Elda
authors: E
authors: Favari
authors: Lucia
authors: L
authors: Magnolo
authors: Sara
authors: S
authors: Simonelli
authors: Maria Pia
authors: MP
authors: Adorni
authors: Raffaella
authors: R
authors: Sallo
authors: Tatiana
authors: T
authors: Fancello
authors: Ivana
authors: I
authors: Zavaroni
authors: Diego
authors: D
authors: Ardigò
authors: Franco
authors: F
authors: Bernini
authors: Laura
authors: L
authors: Calabresi
authors: Guido
authors: G
authors: Franceschini
authors: Patrizia
authors: P
authors: Tarugi
authors: Sebastiano
authors: S
authors: Calandra
authors: Stefano
authors: S
authors: Bertolini
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000091303:Angiopoietin-Like Protein 3; D000075802:Angiopoietin-like Proteins; D042682:Angiopoietins / Q000097:blood / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D002460:Cell Line; D002784:Cholesterol / Q000378:metabolism; D005260:Female; D006801:Humans; D052456:Hypoalphalipoproteinemias / Q000175:diagnosis* / Q000235:genetics / Q000473:pathology*; D006995:Hypobetalipoproteinemias / Q000175:diagnosis* / Q000235:genetics / Q000473:pathology*; D008075:Lipoproteins, HDL / Q000097:blood; D008077:Lipoproteins, LDL / Q000097:blood; D008264:Macrophages / Q000378:metabolism; D008297:Male; D051379:Mice; D008875:Middle Aged; D009154:Mutation; D010375:Pedigree; D014280:Triglycerides / Q000097:blood
chemical_list: C479896:ANGPTL3 protein, human; D000091303:Angiopoietin-Like Protein 3; D000075802:Angiopoietin-like Proteins; D042682:Angiopoietins; D008075:Lipoproteins, HDL; D008077:Lipoproteins, LDL; D014280:Triglycerides; D002784:Cholesterol