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.

METHODS AND 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: Livia Pisciotta, Elda Favari, Lucia Magnolo, Sara Simonelli, Maria Pia Adorni, Raffaella Sallo, Tatiana Fancello, Ivana Zavaroni, Diego Ardigò, Franco Bernini, Laura Calabresi, Guido Franceschini, Patrizia Tarugi, Sebastiano Calandra, Stefano Bertolini
• Journal: Circulation. Cardiovascular genetics (Circ Cardiovasc Genet) Vol. 5 Issue 1 Pg. 42-50 (Feb 01 2012) ISSN: 1942-3268 [Electronic] United States
• PMID: 22062970 (Publication Type: Case Reports, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• ANGPTL3 protein, human
• Angiopoietin-Like Protein 3
• Angiopoietin-like Proteins
• Angiopoietins
• Lipoproteins, HDL
• Lipoproteins, LDL
• Triglycerides
• Cholesterol

Topics

• Aged
• Aged, 80 and over
• Angiopoietin-Like Protein 3
• Angiopoietin-like Proteins
• Angiopoietins (blood, genetics, metabolism)
• Animals
• Cell Line
• Cholesterol (metabolism)
• Female
• Humans
• Hypoalphalipoproteinemias (diagnosis, genetics, pathology)
• Hypobetalipoproteinemias (diagnosis, genetics, pathology)
• Lipoproteins, HDL (blood)
• Lipoproteins, LDL (blood)
• Macrophages (metabolism)
• Male
• Mice
• Middle Aged
• Mutation
• Pedigree
• Triglycerides (blood)