title: Apoa5 Q139X truncation predisposes to late-onset hyperchylomicronemia due to lipoprotein lipase impairment.
abstract: While type 1 hyperlipidemia is associated with lipoprotein lipase or apoCII deficiencies, the etiology of type 5 hyperlipidemia remains largely unknown. We explored a new candidate gene, APOA5, for possible causative mutations in a pedigree of late-onset, vertically transmitted hyperchylomicronemia. A heterozygous Q139X mutation in APOA5 was present in both the proband and his affected son but was absent in 200 controls. It was subsequently found in 2 of 140 cases of hyperchylomicronemia. Haplotype analysis suggested the new Q139X as a founder mutation. Family studies showed that 5 of 9 total Q139X carriers had hyperchylomicronemia, 1 patient being homozygote. Severe hypertriglyceridemia in 8 heterozygotes was strictly associated with the presence on the second allele of 1 of 2 previously described triglyceride-raising minor APOA5 haplotypes. Furthermore, ultracentrifugation fraction analysis indicated in carriers an altered association of Apoa5 truncated and WT proteins to lipoproteins, whereas in normal plasma, Apoa5 associated with VLDL and HDL/LDL fractions. APOB100 kinetic studies in 3 severely dyslipidemic patients with Q139X revealed a major impairment of VLDL catabolism. Lipoprotein lipase activity and mass were dramatically reduced in dyslipidemic carriers, leading to severe lipolysis defect. Our observations strongly support in humans a role for APOA5 in lipolysis regulation and in familial hyperchylomicronemia.
authors.affiliation: Laboratoire de Biochimie, Centre Hospitalier Lyon-Sud, Hospices Civils de Lyon, Pierre-Benite Cedex, France. christophe.marcais@chu-lyon.fr
authors.forename: Christophe
authors.initials: C
authors.lastname: Marçais
authors.forename: Bruno
authors.initials: B
authors.lastname: Verges
authors.forename: Sybil
authors.initials: S
authors.lastname: Charrière
authors.forename: Valérie
authors.initials: V
authors.lastname: Pruneta
authors.forename: Micheline
authors.initials: M
authors.lastname: Merlin
authors.forename: Stéphane
authors.initials: S
authors.lastname: Billon
authors.forename: Laurence
authors.initials: L
authors.lastname: Perrot
authors.forename: Jocelyne
authors.initials: J
authors.lastname: Drai
authors.forename: Agnès
authors.initials: A
authors.lastname: Sassolas
authors.forename: Len A
authors.initials: LA
authors.lastname: Pennacchio
authors.forename: Jamila
authors.initials: J
authors.lastname: Fruchart-Najib
authors.forename: Jean-Charles
authors.initials: JC
authors.lastname: Fruchart
authors.forename: Vincent
authors.initials: V
authors.lastname: Durlach
authors.forename: Philippe
authors.initials: P
authors.lastname: Moulin
mesh_terms: D000595:Amino Acid Sequence / Q000235:genetics; D000072040:Apolipoprotein A-V; D001053:Apolipoproteins / Q000097:blood / Q000235:genetics*; D001054:Apolipoproteins A; D018389:Codon, Nonsense / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D015228:Hypertriglyceridemia / Q000097:blood / Q000201:enzymology / Q000235:genetics*; D008052:Lipid Metabolism, Inborn Errors / Q000097:blood / Q000201:enzymology / Q000235:genetics*; D008066:Lipolysis / Q000235:genetics; D008071:Lipoprotein Lipase / Q000097:blood* / Q000235:genetics; D008074:Lipoproteins / Q000097:blood; D008297:Male; D008875:Middle Aged; D010375:Pedigree; D017354:Point Mutation / Q000235:genetics; D017384:Sequence Deletion / Q000235:genetics; D014280:Triglycerides / Q000097:blood
chemical_list: C437704:APOA5 protein, human; D000072040:Apolipoprotein A-V; D001053:Apolipoproteins; D001054:Apolipoproteins A; D018389:Codon, Nonsense; D008074:Lipoproteins; D014280:Triglycerides; D008071:Lipoprotein Lipase