The Major Molecular Causes of Familial Hypercholesterolemia


Affiliations

  • Ho Chi Minh City Open University, Department of Pharmaceutical and Medical Biotechnology, Faculty of Biotechnology, Ho Chi Minh City, Viet Nam

Abstract

Familial Hypercholesterolemia (FH) is a common dominant disorder of cholesterol metabolism characterized by elevated serum cholesterol level which results in increasing risk of many diseases. The major cause of FH is the loss-of-function in Low Density Lipoprotein Receptor (LDLR), Apolipoprotein B-100 (ApoB-100), Low Density Lipoprotein Receptor Adapter Protein (LDLRAP1), and Proprotein Convertase Subtilisin/Kexin type 9 (PCSK9) gene that revealed to the defects in the uptake and degradation of Low Density Lipoprotein (LDL) via the LDLR pathway. In this review, we have highlighted the molecular disorder in LDLR, ApoB-100, LDLRAP1 and PCSK gene, leading to the possible accession on early diagnosis, screening of FH based on the clinical characteristics, family history, evaluated LDL-Cholesterol levels and recently genetic testing aided, hence molecular based therapy will be applied or recommended to FH patients.

Keywords

Apolipoprotein B-100 (ApoB-100), Familial Hypercholesterolemia, Low Density Lipoprotein Receptor, Low Density Lipoprotein Receptor Adapter Protein, Proprotein Convertase Subtilisin/Kexin Type 9.

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References

Najam O, Ray KK. Familial hypercholesterolemia: A review of the natural history, diagnosis, and management. Cardiol Ther. 2015; 4(1):25–38. Crossref PMid:25769531 PMCid:PMC4472649

Soutar AK, Naoumova RP. Mechanisms of disease: Genetic causes of familial hypercholesterolemia. Nat Clin Pract Cardiovasc Med. 2007; 4(4):214–25. Crossref PMid:17380167

Farrokhi E, Shayesteh F, Asadi Mobarakeh S, Roghani Dehkordi F, Ghatreh Samani K, Hashemzadeh Chaleshtori M. Molecular characterization of Iranian patients with possible familial hypercholesterolemia. Indian J Clin Biochem. 2011; 26(3):244–8. Crossref PMid:22754187 PMCid:PMC3162949

Khachadurian AK. The inheritance of essential Familial Hypercholesterolemia. Am J Med. 1964; 37:402–7. Crossref

Williams RR, Hunt SC, Schumacher MC, Hegele RA, Leppert MF, Ludwig EH, et al. Diagnosing heterozygous familial hypercholesterolemia using new practical criteria validated by molecular genetics. Am J Cardiol. 1993; 72(2):171–6. Crossref

Séguro F, Bongard V, Bérard E, Taraszkiewicz D, Ruidavets JB, Ferrières J. Dutch lipid clinic network low-density lipoprotein cholesterol criteria are associated with long-term mortality in the general population. Arch Cardiovasc Dis. 2015; 108(10):511–8. Crossref PMid:26073227

Goldstein JL, Brown MS. Molecular medicine. The cholesterol quartet. Science. 2001; 292(5520):1310–2. Crossref

Varret M, Abifadel M, Rabès JP, Boileau C. Genetic heterogeneity of autosomal dominant hypercholesterolemia. Clin Genet. 2008; 73(1):1–13. Crossref PMid:18028451

Hopkins PN, Toth PP, Ballantyne CM, Rader DJ. National lipid association expert panel on familial hypercholesterolemia. Familial hypercholesterolemias: Prevalence, genetics, diagnosis and screening recommendations from the National Lipid Association Expert Panel on Familial Hypercholesterolemia. J Clin Lipidol. 2011(3 Suppl); 5:S9– 17. Crossref PMid:21600530

Innerarity TL, Mahley RW, Weisgraber KH, Bersot TP, Krauss RM, Vega GL, et al. Familial defective Apolipoprotein B-100: a mutation of apolipoprotein B that causes hypercholesterolemia. J Lipid Res. 1990; 31(8):1337– 49. PMid:2280177

Walldius G, Jungner I, Holme I, Aastveit AH, Kolar W, Steiner E. High apolipoprotein B, low apolipoprotein A-I, and improvement in the prediction of fatal myocardial infarction (AMORIS study): a prospective study. Lancet. 2001; 358(9298):2026–33. Crossref

Abifadel M, Varret M, Rabès JP, Allard D, Ouguerram K, Devillers M, et al. Mutations in PCSK9 cause autosomal dominant hypercholesterolemia. Nat Genet. 2003; 34(2):154–6. Crossref PMid:12730697

13. Banaszak LJ, Ranatunga WK. The assembly of apoBcontaining lipoproteins: A structural biology point of view. Ann Med. 2008; 40(4):253–67. Crossref PMid:18428019

Horton JD, Cohen JC, Hobbs HH. PCSK9: A convertase that coordinates LDL catabolism. J Lipid Res. 2009; 50(Suppl):S172–7. Crossref PMid:19020338 PMCid:PMC2674748

Brown MS, Goldstein JL. Familial hypercholesterolemia: Defective binding of lipoproteins to cultured fibroblasts associated with impaired regulation of 3-hydroxy-3-methylglutaryl coenzyme A reductase activity. Proc Natl Acad Sci U S A. 1974; 71(3):788–92. Crossref

Francke U, Brown MS, Goldstein JL. Assignment of the human gene for the low density lipoprotein receptor to chromosome 19: synteny of a receptor, a ligand, and a genetic disease. Proc Natl Acad Sci U S A. 1984; 81(9):2826– 30. Crossref PMid:6326146 PMCid:PMC345163

Lindgren V, Luskey KL, Russell DW, Francke U. Human genes involved in cholesterol metabolism: chromosomal mapping of the loci for the low density lipoprotein receptor and 3-hydroxy-3-methylglutaryl-coenzyme A reductase with cDNA probes. Proc Natl Acad Sci U S A. 1985; 82(24):8567– 71. Crossref PMid:3866240 PMCid:PMC390958

Usifo E, Leigh SE, Whittall RA, Lench N, Taylor A, Yeats C, et al. Low-density lipoprotein receptor gene familial hypercholesterolemia variant database: update and pathological assessment. Ann Hum Genet. 2012; 76(5):387–401. Crossref PMid:22881376

Arráiz N, Bermúdez V, Rondon N, Reyes F, Borjas L, Solís E, et al. Novel mutations identification in exon 4 of LDLR gene in patients with moderate hypercholesterolemia in a Venezuelan population. Am J Ther. 2010; 17(3):325–9. Crossref PMid:20019594

Neff D, Ruschitzka F, Hersberger M, Enseleit F, Hürlimann D, Noll G, et al. Detection of a novel exon 4 low-density lipoprotein receptor gene deletion in a swiss family with severe familial hypercholesterolemia. Clin Chem Lab Med. 2003; 41(3):266–71. Crossref PMid:12705331

Hobbs HH, Russell DW, Brown MS, Goldstein JL. The LDL receptor locus in familial hypercholesterolemia: mutational analysis of a membrane protein. Annu Rev Genet. 1990; 24:133–70. Crossref PMid:2088165

Hobbs HH, Brown MS, Goldstein JL. Molecular genetics of the LDL receptor gene in familial hypercholesterolemia. Hum Mutat. 1992; 1:445–66. Crossref PMid:1301956

Varghese MJ. Familial hypercholesterolemia: A review. Annals of Pediatric Cardiology. 2014; 7(2):107–17. Crossref PMid:24987256 PMCid:PMC4070199

Knott TJ, Rall SC Jr, Innerarity TL, Jacobson SF, Urdea MS, Levy-Wilson B, et al. Human apolipoprotein B: Structure of carboxyl-terminal domains, sites of gene expression, and chromosomal localization. Science. 1985; 230(4721):37– 43. Crossref PMid:2994225

Law SW, Lackner KJ, Hospattankar AV, Anchors JM, Sakaguchi AY, Naylor SL, et al. Human apolipoprotein B-100: cloning, analysis of liver mRNA, and assignment of the gene to chromosome 2. Proc Natl Acad Sci U S A. 1985; 82(24):8340–4. Crossref PMid:3001697 PMCid:PMC390911

Soria LF, Ludwig EH, Clarke HR, Vega GL, Grundy SM, Mc Carthy BJ. Association between a specific apolipoprotein B mutation and familial defective apolipoprotein B-100. Proc Natl Acad Sci U S A. 1989; 86(2):587–91. Crossref PMid:2563166 PMCid:PMC286517

Dunning AM, Houlston R, Frostegård J, Revill J, Nilsson J, Hamsten A, et al. Genetic evidence that the putative receptor binding domain of apolipoprotein B (residues 3130 to 3630) is not the only region of the protein involved in interaction with the low density lipoprotein receptor. Biochim Biophys Acta. 1991; 1096(3):231–7. Crossref

Gaffney D, Reid JM, Cameron IM, Vass K, Caslake MJ, Shepherd J, et al. Independent mutations at codon 3500 of the apolipoprotein B gene are associated with hyperlipidemia. Arterioscler Thromb Vasc Biol. 1995; 15(8):1025–9. Crossref PMid:7627691

Pullinger CR, Hennessy LK, Chatterton JE, Liu W, Love JA, Mendel CM, et al. Familial ligand-defective apolipoprotein B. Identification of a new mutation that decreases LDL receptor binding affinity. J Clin Invest. 1995; 95(3):1225–34. Crossref PMid:7883971 PMCid:PMC441461

Borén J, Ekström U, Agren B, Nilsson-Ehle P, Innerarity TL. The molecular mechanism for the genetic disorder familial defective apolipoprotein B100. J Biol Chem. 2001; 276(12):9214–8. Crossref PMid:11115503

Garcia CK, Wilund K, Arca M, Zuliani G, Fellin R, Maioli M, et al. Autosomal recessive hypercholesterolemia caused by mutations in a putative LDL receptor adaptor protein. Science. 2001; 292(5520):1394–8. Crossref PMid:11326085

Sun XM, Patel DD, Acosta JC, Gil J, Soutar AK. Premature senescence in cells from patients with Autosomal Recessive Hypercholesterolemia (ARH): Evidence for a role for ARH in mitosis. Arterioscler ThrombVasc Biol. 2011; 31(10):2270–7. Crossref PMid:21778424

Soutar AK, Naoumova RP. Autosomal Recessive Hypercholesterolemia. Semin Vasc Med. 2004; 4(3):241–8. Crossref PMid:15630633

Tada H, Kawashiri MA, Ohtani R, Noguchi T, Nakanishi C, Konno T, et al. A novel type of familial hypercholesterolemia: Double heterozygous mutations in LDL receptor and LDL receptor adaptor protein 1 gene. Atherosclerosis. 2011; 219(2):663–6. Crossref PMid:21872251

Horton JD, Cohen JC, Hobbs HH. Molecular biology of PCSK9: its role in LDL metabolism. Trends Biochem Sci. 2007; 32(2):71–7. Crossref PMid:17215125 PMCid:PMC2711871

Peterson AS, Fong LG, Young SG. PCSK9 function and physiology. J Lipid Res. 2008; 49(6):1152–6. Crossref PMid:18375913 PMCid:PMC2386899

Hartgers ML, Ray KK, Hovingh GK. New approaches in detection and treatment of familial hypercholesterolemia. Curr Cardiol Rep. 2015; 17(12):109. Crossref PMid:26482752 PMCid:PMC4611021

Stancu C, Sima A. Statins: mechanism of action and effects. J Cell Mol Med. 2001; 5(4):378–87. Crossref PMid:12067471

Endo A. A historical perspective on the discovery of statins. Proc Jpn Acad Ser B Phys Biol Sci. 2010; 86(5):484–93. Crossref PMid:20467214 PMCid:PMC3108295

Wong E, Goldberg T. Mipomersen (kynamro): A novel antisense oligonucleotide inhibitor for the management of homozygous familial hypercholesterolemia. P T. 2014; 39(2):119–22.

Agarwala A, Jones P, Nambi V. The role of antisense oligonucleotide therapy in patients with familial hypercholesterolemia: risks, benefits, and management recommendations. Curr Atheroscler Rep. 2015; 17(1):467. Crossref PMid:25398643

Jamil H, Dickson JK Jr, Chu CH, Lago MW, Rinehart JK, Biller SA, et al. Microsomal triglyceride transfer protein. Specificity of lipid binding and transport. J Biol Chem. 1995; 270(12):6549–54. Crossref PMid:7896791

Davis KA, Miyares MA. Lomitapide: A novel agent for the treatment of homozygous familial hypercholesterolemia. Am J Health Syst Pharm. 2014; 71(12):1001–8. Crossref PMid:24865757

Zimmerman MP. How do PCSK9 inhibitors stack up to statins for low-density lipoprotein cholesterol control? American Health and Drug Benefits. 2015; 8(8):436–42. PMid:26702335 PMCid:PMC4684634

Paton DM. PCSK9 inhibitors: Monoclonal antibodies for the treatment of hypercholesterolemia. Drugs Today (Barc). 2016; 52(3):183–92. Crossref PMid:27186592

Chaudhary R, Garg J, Shah N, Sumner A. PCSK9 inhibitors: A new era of lipid lowering therapy. World J Cardiol.2017; 9(2):76–91. Crossref PMid:28289523 PMCid:PMC5329749

Burke AC, Dron JS, Hegele RA, Huff MW. PCSK9: Regulation and target for drug development for dyslipidemia. Annu Rev Pharmacol Toxico. 2017; 57:223–44. Crossref PMid:27575716


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