Abstract
Rare monogenic hyperchylomicronemia is caused by loss-of-function mutations in genes involved in the catabolism of triglyceride-rich lipoproteins, including the lipoprotein lipase gene, LPL. Clinical hallmarks of this condition are eruptive xanthomas, recurrent pancreatitis and abdominal pain. Patients with LPL deficiency and severe or recurrent pancreatitis are eligible for the first gene therapy treatment approved by the European Union. Therefore the precise molecular diagnosis of familial hyperchylomicronemia may affect treatment decisions. We present a 57-year-old male patient with excessive hypertriglyceridemia despite intensive lipid-lowering therapy. Abdominal sonography showed signs of chronic pancreatitis. Direct DNA sequencing and cloning revealed two novel missense variants, c.1302A>T and c.1306G>A, in exon 8 of the LPL gene coexisting on the same allele. The variants result in the amino-acid exchanges p.(Lys434Asn) and p.(Gly436Arg). They are located in the carboxy-terminal domain of lipoprotein lipase that interacts with the glycosylphosphatidylinositol-anchored HDL-binding protein (GPIHBP1) and are likely of functional relevance. No further relevant mutations were found by direct sequencing of the genes for APOA5, APOC2, LMF1 and GPIHBP1. We conclude that heterozygosity for damaging mutations of LPL may be sufficient to produce severe hypertriglyceridemia and that chylomicronemia may be transmitted in a dominant manner, at least in some families.
Similar content being viewed by others
Login or create a free account to read this content
Gain free access to this article, as well as selected content from this journal and more on nature.com
or
References
Murad MH, Hazem A, Coto-Yglesias F et al: The association of hypertriglyceridemia with cardiovascular events and pancreatitis: a systematic review and meta-analysis. BMC Endocr Disord 2012; 12: 2.
Hegele RA, Ginsberg HN, Chapman MJ et al: The polygenic nature of hypertriglyceridaemia: implications for definition, diagnosis, and management. Lancet Diab Endocrinol 2014; 2: 655–666.
Surendran RP, Visser ME, Heemelaar S et al: Mutations in LPL, APOC2, APOA5, GPIHBP1 and LMF1 in patients with severe hypertriglyceridaemia. J Intern Med 2012; 272: 185–196.
Teslovich TM, Musunuru K, Smith AV et al: Biological, clinical and population relevance of 95 loci for blood lipids. Nature 2010; 466: 707–713.
Wang J, Ban MR, Zou GY et al: Polygenic determinants of severe hypertriglyceridemia. Hum Mol Genet 2008; 17: 2894–2899.
Wang J, Cao H, Ban MR et al: Resequencing genomic DNA of patients with severe hypertriglyceridemia (MIM 144650). Arterioscler Thromb Vasc Biol 2007; 27: 2450–2455.
Wright WT, Young IS, Nicholls DP, Graham CA : Genetic screening of the LPL gene in hypertriglyceridaemic patients. Atherosclerosis 2008; 199: 187–192.
Kuivenhoven JA, Hegele RA : Mining the genome for lipid genes. Biochimica et Biophysica Acta 2014; 1842: 1993–2009.
Scherer J, Singh VP, Pitchumoni CS, Yadav D : Issues in hypertriglyceridemic pancreatitis: an update. J Clin Gastroenterol 2014; 48: 195–203.
Gaudet D, Methot J, Kastelein J : Gene therapy for lipoprotein lipase deficiency. Curr Opin Lipidol 2012; 23: 310–320.
Beigneux AP, Davies BS, Gin P et al: Glycosylphosphatidylinositol-anchored high-density lipoprotein-binding protein 1 plays a critical role in the lipolytic processing of chylomicrons. Cell Metab 2007; 5: 279–291.
Adzhubei IA, Schmidt S, Peshkin L et al: A method and server for predicting damaging missense mutations. Nat Methods 2010; 7: 248–249.
Schwarz JM, Rodelsperger C, Schuelke M, Seelow D : MutationTaster evaluates disease-causing potential of sequence alterations. Nat Methods 2010; 7: 575–576.
Ginzinger DG, Lewis ME, Ma Y, Jones BR, Liu G, Jones SD : A mutation in the lipoprotein lipase gene is the molecular basis of chylomicronemia in a colony of domestic cats. J Clin Investig 1996; 97: 1257–1266.
Gin P, Goulbourne CN, Adeyo O et al: Chylomicronemia mutations yield new insights into interactions between lipoprotein lipase and GPIHBP1. Hum Mol Genet 2012; 21: 2961–2972.
Johansen CT, Wang J, Lanktree MB et al: Excess of rare variants in genes identified by genome-wide association study of hypertriglyceridemia. Nat Genet 2010; 42: 684–687.
Author information
Authors and Affiliations
Corresponding authors
Ethics declarations
Competing interests
UK received honoraria for lectures from Fresenius medical care, Sanofi and B. Braun. The remaining authors declare no conflict of interest.
Rights and permissions
About this article
Cite this article
Kassner, U., Salewsky, B., Wühle-Demuth, M. et al. Severe hypertriglyceridemia in a patient heterozygous for a lipoprotein lipase gene allele with two novel missense variants. Eur J Hum Genet 23, 1259–1261 (2015). https://doi.org/10.1038/ejhg.2014.295
Received:
Revised:
Accepted:
Published:
Issue date:
DOI: https://doi.org/10.1038/ejhg.2014.295
