Apoa5 Q139X truncation predisposes to late-onset hyperchylomicronemia due to lipoprotein lipase impairment.
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.
Marçais
Christophe
C
Laboratoire de Biochimie, Centre Hospitalier Lyon-Sud, Hospices Civils de Lyon, Pierre-Benite Cedex, France. christophe.marcais@chu-lyon.fr
Verges
Bruno
B
Charrière
Sybil
S
Pruneta
Valérie
V
Merlin
Micheline
M
Billon
Stéphane
S
Perrot
Laurence
L
Drai
Jocelyne
J
Sassolas
Agnès
A
Pennacchio
Len A
LA
Fruchart-Najib
Jamila
J
Fruchart
Jean-Charles
JC
Durlach
Vincent
V
Moulin
Philippe
P
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
C437704:APOA5 protein, human; D000072040:Apolipoprotein A-V; D001053:Apolipoproteins; D001054:Apolipoproteins A; D018389:Codon, Nonsense; D008074:Lipoproteins; D014280:Triglycerides; D008071:Lipoprotein Lipase