Asian Journal of Pharmaceutical Research and Health Care

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The Major Molecular Causes of Familial Hypercholesterolemia


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

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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  • 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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  • The Major Molecular Causes of Familial Hypercholesterolemia

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Authors

Phuong Kim Truong
Department of Pharmaceutical and Medical Biotechnology, Faculty of Biotechnology, Ho Chi Minh City Open University, Ho Chi Minh City, Viet Nam
Thuan Duc Lao
Department of Pharmaceutical and Medical Biotechnology, Faculty of Biotechnology, Ho Chi Minh City Open University, Ho Chi Minh City, Viet Nam
Thuy Huyen Ai Le
Department of Pharmaceutical and Medical Biotechnology, Faculty of Biotechnology, Ho Chi Minh City Open University, 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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DOI: https://doi.org/10.18311/ajprhc%2F2018%2F20031