on December 9, 2004
Published online before print December 9, 2004, doi: 10.1161/01.ATV.0000153087.36428.dd
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Submitted on August 3, 2004
Accepted on November 26, 2004
Inherited Apolipoprotein A-V Deficiency in Severe Hypertriglyceridemia
Claudio Priore Oliva ;
From the Department of Biomedical Sciences (C.P.O., P.T., S.C.), University of Modena and Reggio Emilia; Department of Internal Medicine (L.P., A.B., S.B.), University of Genova; Department of Pediatrics (G.L.V., M.P.S.), University of Catania; National Institute of Health (A.C.), Rome; Department of Pharmacological Sciences (A.C.), University of Milan, Italy.
* To whom correspondence should be addressed. E-mail: sebcal{at}unimore.it.
Objective--Mutations in LPL or APOC2 genes are recognized causes of inherited forms of severe hypertriglyceridemia. However, some hypertrigliceridemic patients do not have mutations in either of these genes. Because inactivation or hyperexpression of APOA5 gene, encoding apolipoprotein A-V (apoA-V), causes a marked increase or decrease of plasma triglycerides in mice, and because some common polymorphisms of this gene affect plasma triglycerides in humans, we have hypothesized that loss of function mutations in APOA5 gene might cause hypertriglyceridemia.
Methods and Results--We sequenced APOA5 gene in 10 hypertriglyceridemic patients in whom mutations in LPL and APOC2 genes had been excluded. One of them was found to be homozygous for a mutation in APOA5 gene (c.433 C>T, Q145X), predicted to generate a truncated apoA-V devoid of key functional domains. The plasma of this patient was found to activate LPL in vitro less efficiently than control plasma, thus suggesting that apoA-V might be an activator of LPL. Ten carriers of Q145X mutation were found in the patient’s family; 5 of them had mild hypertriglyceridemia.
Conclusions--As predicted from animal studies, apoA-V deficiency is associated with severe hypertriglyceridemia in humans. This observation suggests that apoA-V regulates the secretion and/or catabolism of triglyceride-rich lipoproteins.
Key words: apolipoprotein A-V deficiency • hypertriglyceridemia • hyperchylomicronemia • APOA5 gene • nonsense mutation
This article has been cited by other articles:
 |
|
 |
|
  B. Dorfmeister, W.W. Zeng, A. Dichlberger, S.K. Nilsson, F.G. Schaap, J.A. Hubacek, M. Merkel, J.A. Cooper, A. Lookene, W. Putt, et al. Effects of Six APOA5 Variants, Identified in Patients With Severe Hypertriglyceridemia, on In Vitro Lipoprotein Lipase Activity and Receptor Binding Arterioscler. Thromb. Vasc. Biol., October 1, 2008; 28(10): 1866 - 1871. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. M. Mansouri, E. Bauge, P. Gervois, J. Fruchart-Najib, C. Fievet, B. Staels, and J.-C. Fruchart Atheroprotective Effect of Human Apolipoprotein A5 in a Mouse Model of Mixed Dyslipidemia Circ. Res., August 29, 2008; 103(5): 450 - 453. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. Gerritsen, C. C. van der Hoogt, F. G. Schaap, P. J. Voshol, K. E. Kypreos, N. Maeda, A. K. Groen, L. M. Havekes, P. C. N. Rensen, and K. W. van Dijk ApoE2-associated hypertriglyceridemia is ameliorated by increased levels of apoA-V but unaffected by apoC-III deficiency J. Lipid Res., May 1, 2008; 49(5): 1048 - 1055. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. Nelbach, X. Shu, R. J. Konrad, R. O. Ryan, and T. M. Forte Effect of apolipoprotein A-V on plasma triglyceride, lipoprotein size, and composition in genetically engineered mice J. Lipid Res., March 1, 2008; 49(3): 572 - 580. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Wang, H. Cao, M. R. Ban, B. A. Kennedy, S. Zhu, S. Anand, S. Yusuf, R. L. Pollex, and R. A. Hegele Resequencing Genomic DNA of Patients With Severe Hypertriglyceridemia (MIM 144650) Arterioscler. Thromb. Vasc. Biol., November 1, 2007; 27(11): 2450 - 2455. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Kahri, J. Fruchart-Najib, N. Matikainen, J.-C. Fruchart, J. Vakkilainen, and M.-R. Taskinen The Increase of Apolipoprotein A-V During Postprandial Lipemia Parallels the Response of Triglyceride-Rich Lipoproteins in Type 2 Diabetes: No relationship between apoA-V and postheparin plasma lipolytic activity Diabetes Care, August 1, 2007; 30(8): 2083 - 2085. [Full Text] [PDF]
|
|
|
|
|
|
X. Shu, J. Chan, R. O. Ryan, and T. M. Forte Apolipoprotein A-V association with intracellular lipid droplets J. Lipid Res., July 1, 2007; 48(7): 1445 - 1450. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Albrechtsen, S. Castella, G. Andersen, T. Hansen, O. Pedersen, and R. Nielsen A Bayesian Multilocus Association Method: Allowing for Higher-Order Interaction in Association Studies Genetics, June 1, 2007; 176(2): 1197 - 1208. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. A. Beckstead, K. Wong, V. Gupta, C.-P. L. Wan, V. R. Cook, R. B. Weinberg, P. M. M. Weers, and R. O. Ryan The C Terminus of Apolipoprotein A-V Modulates Lipid-binding Activity J. Biol. Chem., May 25, 2007; 282(21): 15484 - 15489. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Garg and V. Simha Update on Dyslipidemia J. Clin. Endocrinol. Metab., May 1, 2007; 92(5): 1581 - 1589. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. G. Schaap, M. C. Nierman, J. F. P. Berbee, H. Hattori, P. J. Talmud, S. F. C. Vaessen, P. C. N. Rensen, R. A. F. M. Chamuleau, J. A. Kuivenhoven, and A. K. Groen Evidence for a complex relationship between apoA-V and apoC-III in patients with severe hypertriglyceridemia J. Lipid Res., October 1, 2006; 47(10): 2333 - 2339. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Guardiola, R. Ferre, J. Salazar, C. Alonso-Villaverde, B. Coll, S. Parra, L. Masana, and J. Ribalta Protease Inhibitor-Associated Dyslipidemia in HIV-Infected Patients Is Strongly Influenced by the APOA5-1131T->C Gene Variation Clin. Chem., October 1, 2006; 52(10): 1914 - 1919. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
W. E. Alborn, M. G. Johnson, M. J. Prince, and R. J. Konrad Definitive N-terminal protein sequence and further characterization of the novel apolipoprotein a5 in human serum. Clin. Chem., March 1, 2006; 52(3): 514 - 517. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. C.N. Rensen, K. W. van Dijk, and L. M. Havekes Apolipoprotein AV: Low Concentration, High Impact Arterioscler. Thromb. Vasc. Biol., December 1, 2005; 25(12): 2445 - 2447. [Full Text] [PDF]
|
|
|
|
|
|
R. M. Krauss Dietary and Genetic Probes of Atherogenic Dyslipidemia Arterioscler. Thromb. Vasc. Biol., November 1, 2005; 25(11): 2265 - 2272. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Ishihara, T. Kujiraoka, T. Iwasaki, M. Nagano, M. Takano, J. Ishii, M. Tsuji, H. Ide, I. P. Miller, N. E. Miller, et al. A sandwich enzyme-linked immunosorbent assay for human plasma apolipoprotein A-V concentration J. Lipid Res., September 1, 2005; 46(9): 2015 - 2022. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. E. Schultze, W. E. Alborn, R. K. Newton, and R. J. Konrad Administration of a PPAR{alpha} agonist increases serum apolipoprotein A-V levels and the apolipoprotein A-V/apolipoprotein C-III ratio J. Lipid Res., August 1, 2005; 46(8): 1591 - 1595. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
X. Prieur, T. Huby, H. Coste, F. G. Schaap, M. J. Chapman, and J. C. Rodriguez Thyroid Hormone Regulates the Hypotriglyceridemic Gene APOA5 J. Biol. Chem., July 29, 2005; 280(30): 27533 - 27543. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
V. Pruneta-Deloche, C. Marcais, L. Perrot, A. Sassolas, M. Delay, B. Estour, M. Lagarde, and P. Moulin Combination of Circulating Antilipoprotein Lipase (Anti-LPL) Antibody and Heterozygous S172 fsX179 Mutation of LPL Gene Leading to Chronic Hyperchylomicronemia J. Clin. Endocrinol. Metab., July 1, 2005; 90(7): 3995 - 3998. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. Frances, D. Corella, J. V. Sorli, M. Guillen, J. I. Gonzalez, and O. Portoles Validating a Rapid Method for Detecting Common Polymorphisms in the APOA5 Gene by Melting Curve Analysis Using LightTyper Clin. Chem., July 1, 2005; 51(7): 1279 - 1282. [Full Text] [PDF]
|
|