Identification and Characterization of Two Novel Compounds: Heterozygous Variants of in Two Pedigrees With Type I Hyperlipoproteinemia

Overview

Journal Front Endocrinol (Lausanne)

Specialty Endocrinology

Date 2022 Aug 4

PMID 35923617

Authors

Shuping Wang

Yiping Cheng

Yingzhou Shi

Wanyi Zhao

Ling Gao

Li Fang

Xiaolong Jin

Xiaoyan Han

Qiuying Sun

Guimei Li

Jiajun Zhao

Chao Xu

Affiliations

Soon will be listed here.

Abstract

Background: Type I hyperlipoproteinemia, characterized by severe hypertriglyceridemia, is caused mainly by loss-of-function mutation of the () gene. To date, more than 200 mutations in the gene have been reported, while only a limited number of mutations have been evaluated for pathogenesis.

Objective: This study aims to explore the molecular mechanisms underlying lipoprotein lipase deficiency in two pedigrees with type 1 hyperlipoproteinemia.

Methods: We conducted a systematic clinical and genetic analysis of two pedigrees with type 1 hyperlipoproteinemia. Postheparin plasma of all the members was used for the LPL activity analysis. studies were performed in HEK-293T cells that were transiently transfected with wild-type or variant plasmids. Furthermore, the production and activity of LPL were analyzed in cell lysates or culture medium.

Results: Proband 1 developed acute pancreatitis in youth, and her serum triglycerides (TGs) continued to be at an ultrahigh level, despite the application of various lipid-lowering drugs. Proband 2 was diagnosed with type 1 hyperlipoproteinemia at 9 months of age, and his serum TG levels were mildly elevated with treatment. Two novel compound heterozygous variants of (c.3G>C, p. M1? and c.835_836delCT, p. L279Vfs*3, c.188C>T, p. Ser63Phe and c.662T>C, p. Ile221Thr) were identified in the two probands. The postheparin LPL activity of probands 1 and 2 showed decreases of 72.22 ± 9.46% (p<0.01) and 54.60 ± 9.03% (p<0.01), respectively, compared with the control. studies showed a substantial reduction in the expression or enzyme activity of LPL in the variants.

Conclusions: Two novel compound heterozygous variants of induced defects in the expression and function of LPL and caused type I hyperlipoproteinemia. The functional characterization of these variants was in keeping with the postulated mutant activity.

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References

Chen W, Yang Q, Li X, Shi X, Pu N, Lu G . Identification of a novel and heterozygous LMF1 nonsense mutation in an acute pancreatitis patient with severe hypertriglyceridemia, severe obesity and heavy smoking. Lipids Health Dis. 2019; 18(1):68. PMC: 6421687. DOI: 10.1186/s12944-019-1012-9. View

Deeb S, Peng R . Structure of the human lipoprotein lipase gene. Biochemistry. 1989; 28(10):4131-5. DOI: 10.1021/bi00436a001. View

Rodrigues R, Artieda M, Tejedor D, Martinez A, Konstantinova P, Petry H . Pathogenic classification of LPL gene variants reported to be associated with LPL deficiency. J Clin Lipidol. 2016; 10(2):394-409. DOI: 10.1016/j.jacl.2015.12.015. View

Emmerich J, Beg O, Peterson J, Previato L, Brunzell J, BREWER Jr H . Human lipoprotein lipase. Analysis of the catalytic triad by site-directed mutagenesis of Ser-132, Asp-156, and His-241. J Biol Chem. 1992; 267(6):4161-5. View

Hoffmann M, Jacob S, Luft D, Schmulling R, Rett K, Marz W . Type I hyperlipoproteinemia due to a novel loss of function mutation of lipoprotein lipase, Cys(239)-->Trp, associated with recurrent severe pancreatitis. J Clin Endocrinol Metab. 2001; 85(12):4795-8. DOI: 10.1210/jcem.85.12.7069. View

Gilbert B, Rouis M, Griglio S, de Lumley L, LAPLAUD P . Lipoprotein lipase (LPL) deficiency: a new patient homozygote for the preponderant mutation Gly188Glu in the human LPL gene and review of reported mutations: 75 % are clustered in exons 5 and 6. Ann Genet. 2001; 44(1):25-32. DOI: 10.1016/s0003-3995(01)01037-1. View

Lookene A, Groot N, Kastelein J, Olivecrona G, Bruin T . Mutation of tryptophan residues in lipoprotein lipase. Effects on stability, immunoreactivity, and catalytic properties. J Biol Chem. 1997; 272(2):766-72. DOI: 10.1074/jbc.272.2.766. View

Yu X, Zhao T, Wang L, Liu Z, Zhang C, Chen R . A novel substitution at the translation initiator codon (ATG-->ATC) of the lipoprotein lipase gene is mainly responsible for lipoprotein lipase deficiency in a patient with severe hypertriglyceridemia and recurrent pancreatitis. Biochem Biophys Res Commun. 2006; 341(1):82-7. DOI: 10.1016/j.bbrc.2005.12.165. View

Caddeo A, Mancina R, Pirazzi C, Russo C, Sasidharan K, Sandstedt J . Molecular analysis of three known and one novel LPL variants in patients with type I hyperlipoproteinemia. Nutr Metab Cardiovasc Dis. 2017; 28(2):158-164. DOI: 10.1016/j.numecd.2017.11.003. View

10.

Plengpanich W, Kiateprungvej A, Charoen S, Khovidhunkit W . Clinical and functional studies of two novel variants in the LPL gene in subjects with severe hypertriglyceridemia. Clin Chim Acta. 2018; 487:22-27. DOI: 10.1016/j.cca.2018.08.041. View

11.

Wang H, Eckel R . Lipoprotein lipase: from gene to obesity. Am J Physiol Endocrinol Metab. 2009; 297(2):E271-88. DOI: 10.1152/ajpendo.90920.2008. View

12.

Henderson H, Ma Y, Hassan M, Monsalve M, Marais A, Winkler F . Amino acid substitution (Ile194----Thr) in exon 5 of the lipoprotein lipase gene causes lipoprotein lipase deficiency in three unrelated probands. Support for a multicentric origin. J Clin Invest. 1991; 87(6):2005-11. PMC: 296955. DOI: 10.1172/JCI115229. View

13.

Athyros V, Katsiki N, Doumas M, Karagiannis A, Mikhailidis D . Effect of tobacco smoking and smoking cessation on plasma lipoproteins and associated major cardiovascular risk factors: a narrative review. Curr Med Res Opin. 2013; 29(10):1263-74. DOI: 10.1185/03007995.2013.827566. View

14.

Cheng Y, Sun Y, Ji Y, Jiang D, Teng G, Zhou X . Novel compound variants of the AR and MAP3K1 genes are related to the clinical heterogeneity of androgen insensitivity syndrome. Biosci Rep. 2020; 40(5). PMC: 7953519. DOI: 10.1042/BSR20200616. View

15.

Khovidhunkit W, Charoen S, Kiateprungvej A, Chartyingcharoen P, Muanpetch S, Plengpanich W . Rare and common variants in LPL and APOA5 in Thai subjects with severe hypertriglyceridemia: A resequencing approach. J Clin Lipidol. 2016; 10(3):505-511.e1. DOI: 10.1016/j.jacl.2015.11.007. View

16.

Li X, Yang Q, Shi X, Chen W, Pu N, Li W . Compound but non-linked heterozygous p.W14X and p.L279 V LPL gene mutations in a Chinese patient with long-term severe hypertriglyceridemia and recurrent acute pancreatitis. Lipids Health Dis. 2018; 17(1):144. PMC: 6009947. DOI: 10.1186/s12944-018-0789-2. View

17.

Evans D, Arzer J, Aberle J, Beil F . Rare variants in the lipoprotein lipase (LPL) gene are common in hypertriglyceridemia but rare in Type III hyperlipidemia. Atherosclerosis. 2010; 214(2):386-90. DOI: 10.1016/j.atherosclerosis.2010.11.026. View

18.

Rioja J, Ariza M, Garcia-Casares N, Coca-Prieto I, Arrobas T, Muniz-Grijalvo O . Evaluation of the chylomicron-TG to VLDL-TG ratio for type I hyperlipoproteinemia diagnostic. Eur J Clin Invest. 2020; 50(12):e13345. DOI: 10.1111/eci.13345. View

19.

Chen T, Xie S, Jin R, Huang Z . A novel lipoprotein lipase gene missense mutation in Chinese patients with severe hypertriglyceridemia and pancreatitis. Lipids Health Dis. 2014; 13:52. PMC: 3983885. DOI: 10.1186/1476-511X-13-52. View

20.

Kobayashi Y, Nakajima T, Inoue I . Molecular modeling of the dimeric structure of human lipoprotein lipase and functional studies of the carboxyl-terminal domain. Eur J Biochem. 2002; 269(18):4701-10. DOI: 10.1046/j.1432-1033.2002.03179.x. View