Mechanisms of Disease: genetic causes of familial hypercholesterolemia


Familial hypercholesterolemia (FH) is characterized by raised serum LDL cholesterol levels, which result in excess deposition of cholesterol in tissues, leading to accelerated atherosclerosis and increased risk of premature coronary heart disease. FH results from defects in the hepatic uptake and degradation of LDL via the LDL-receptor pathway, commonly caused by a loss-of-function mutation in the LDL-receptor gene (LDLR) or by a mutation in the gene encoding apolipoprotein B (APOB). FH is primarily an autosomal dominant disorder with a gene–dosage effect. An autosomal recessive form of FH caused by loss-of-function mutations in LDLRAP1, which encodes a protein required for clathrin-mediated internalization of the LDL receptor by liver cells, has also been documented. The most recent addition to the database of genes in which defects cause FH is one encoding a member of the proprotein convertase family, PCSK9. Rare dominant gain-of-function mutations in PCSK9 cosegregate with hypercholesterolemia, and one mutation is associated with a particularly severe FH phenotype. Expression of PCSK9 normally downregulates the LDL-receptor pathway by indirectly causing degradation of LDL-receptor protein, and loss-of-function mutations in PCSK9 result in low plasma LDL levels. Thus, PCSK9 is an attractive target for new drugs aimed at lowering serum LDL cholesterol, which should have additive lipid-lowering effects to the statins currently used.

Key Points

  • Familial hypercholesterolemia (FH) is usually inherited as an autosomal dominant disorder caused by defective clearance of LDL from the circulation that occurs with a frequency of about 1/500

  • Pioneering studies by Brown and Goldstein revealed that FH was usually caused by defective function of a cell-surface receptor for LDL caused by mutations in LDLR

  • Subsequent work has revealed that there are numerous different mutations in the LDL-receptor protein, but these do not explain the variability in the severity of clinical symptoms in heterozygous patients, and the fact that environmental factors are also important

  • Not all patients with clinical FH have mutations in LDLR; mutations in APOB, PCSK9 and LDLRAP1 can affect LDL-receptor function in vivo

  • Diagnosis of FH is important to reduce premature coronary heart disease, but genetic screening for FH is hampered by the large number of different mutations

  • Cascade screening of affected relatives of index patients has already increased rates of diagnosis and treatment of FH in some countries; population screening, however, is probably not cost-effective

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Figure 1: Dominant pattern of inheritance of familial hypercholesterolemia due to mutations in the LDL-receptor gene (LDLR)
Figure 2: The LDL-receptor pathway for uptake and degradation of LDL
Figure 3: The LDLR gene
Figure 4: Autosomal recessive hypercholesterolemia
Figure 5: Severe phenotype in patients heterozygous for the Asp374Tyr mutation in the PCSK9 protein
Figure 6: PCSK9 variants associated with plasma LDL cholesterol concentration


  1. 1

    Goldstein JL et al. (2001) Familial hypercholesterolemia. In The Metabolic and Molecular Bases of Inherited Disease, edn 8, 2863–2913 (Eds Scriver CS et al.) New York: McGraw-Hill Book Co.

    Google Scholar 

  2. 2

    Khachadurian AK (1964) The inheritance of essential familial hypercholesterolemia. Am J Med 37: 402–407

    CAS  PubMed  Google Scholar 

  3. 3

    Arca M et al. (2002) Autosomal recessive hypercholesterolaemia in Sardinia, Italy, and mutations in ARH: a clinical and molecular genetic analysis. Lancet 359: 841–847

    CAS  PubMed  Google Scholar 

  4. 4

    Naoumova RP et al. (2004) Autosomal recessive hypercholesterolaemia: long-term follow up and response to treatment. Atherosclerosis 174: 165–172

    CAS  PubMed  Google Scholar 

  5. 5

    Naoumova RP et al. (2005) Severe hypercholesterolemia in four British families with the D374Y mutation in the PCSK9 gene: long-term follow-up and treatment response. Arterioscler Thromb Vasc Biol 25: 2654–2660

    CAS  PubMed  Google Scholar 

  6. 6

    Langer T et al. (1972) The metabolism of low density lipoprotein in familial type II hyperlipoproteinemia. J Clin Invest 51: 1528–1536

    CAS  PubMed  PubMed Central  Google Scholar 

  7. 7

    Thompson GR et al. (1977) Non-steady-state studies of low-density-lipoprotein turnover in familial hypercholesterolaemia. Clin Sci Mol Med 52: 361–369

    CAS  PubMed  Google Scholar 

  8. 8

    Goldstein JL and Brown MS (1973) Familial hypercholesterolemia: identification of a defect in the regulation of 3-hydroxy-3-methylglutaryl coenzyme A reductase activity associated with overproduction of cholesterol. Proc Natl Acad Sci USA 70: 2084–2088

    Google Scholar 

  9. 9

    Brown MS and Goldstein JL (1974) 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 USA 71: 788–792

    CAS  PubMed  Google Scholar 

  10. 10

    Brown MS and Goldstein JL (1986) A receptor-mediated pathway for cholesterol homeostasis. Science 232: 34–47

    CAS  PubMed  Google Scholar 

  11. 11

    Schneider WJ et al. (1982) Purification of the low density lipoprotein receptor, an acidic glycoprotein of 164,000 molecular weight. J Biol Chem 257: 2664–2673

    CAS  PubMed  Google Scholar 

  12. 12

    Beisiegel U et al. (1981) Monoclonal antibodies to the low density lipoprotein receptor as probes for study of receptor-mediated endocytosis and the genetics of familial hypercholesterolemia. J Biol Chem 256: 11923–11931

    CAS  PubMed  Google Scholar 

  13. 13

    Tolleshaug H et al. (1982) Posttranslational processing of the LDL receptor and its genetic disruption in familial hypercholesterolemia. Cell 30: 715–724

    CAS  PubMed  Google Scholar 

  14. 14

    Hobbs HH et al. (1990) The LDL receptor locus in familial hypercholesterolemia: mutational analysis of a membrane protein. Annu Rev Genet 24: 133–170

    CAS  PubMed  Google Scholar 

  15. 15

    Yamamoto T et al. (1984) The human LDL receptor: a cysteine-rich protein with multiple Alu sequences in its mRNA. Cell 39: 27–38

    CAS  PubMed  Google Scholar 

  16. 16

    Sudhof TC et al. (1985) The LDL receptor gene: a mosaic of exons shared with different proteins. Science 228: 815–822

    CAS  PubMed  PubMed Central  Google Scholar 

  17. 17

    Lehrman MA et al. (1985) Mutation in LDL receptor: Alu-Alu recombination deletes exons encoding transmembrane and cytoplasmic domains. Science 227: 140–146

    CAS  PubMed  PubMed Central  Google Scholar 

  18. 18

    Yang T et al. (2002) Crucial step in cholesterol homeostasis: sterols promote binding of SCAP to INSIG-1, a membrane protein that facilitates retention of SREBPs in ER. Cell 110: 489–500

    CAS  PubMed  Google Scholar 

  19. 19

    Heath KE et al. (2001) Low-density lipoprotein receptor gene (LDLR) world-wide website in familial hypercholesterolaemia: update, new features and mutation analysis. Atherosclerosis 154: 243–246

    CAS  PubMed  Google Scholar 

  20. 20

    Villeger L et al. (2002) The UMD-LDLR database: additions to the software and 490 new entries to the database. Hum Mutat 20: 81–87

    CAS  PubMed  Google Scholar 

  21. 21

    Stenson PD et al. (2003) Human Gene Mutation Database (HGMD): 2003 update. Hum Mutat 21: 577–581

    CAS  PubMed  Google Scholar 

  22. 22

    Schouten JP et al. (2002) Relative quantification of 40 nucleic acid sequences by multiplex ligation-dependent probe amplification. Nucleic Acids Res 30: e57

    PubMed  PubMed Central  Google Scholar 

  23. 23

    Davis CG et al. (1986) The J.D. mutation in familial hypercholesterolemia: amino acid substitution in cytoplasmic domain impedes internalization of LDL receptors. Cell 45: 15–24

    CAS  PubMed  Google Scholar 

  24. 24

    Lombardi P et al. (1997) The T705I mutation of the low density lipoprotein receptor gene (FH Paris-9) does not cause familial hypercholesterolemia. Hum Genet 99: 106–107

    CAS  PubMed  Google Scholar 

  25. 25

    Naoumova RP et al. (2004) Genetic diagnosis of familial hypercholesterolaemia: a mutation and a rare non-pathogenic amino acid variant in the same family. Atherosclerosis 174: 69–71

    Google Scholar 

  26. 26

    Amsellem S et al. (2002) Intronic mutations outside of Alu-repeat-rich domains of the LDL receptor gene are a cause of familial hypercholesterolemia. Hum Genet 111: 501–510

    CAS  PubMed  Google Scholar 

  27. 27

    Sun XM et al. (1995) Characterization of a splice-site mutation in the gene for the LDL receptor associated with an unpredictably severe clinical phenotype in English patients with heterozygous FH. Arterioscler Thromb Vasc Biol 15: 219–227

    CAS  PubMed  Google Scholar 

  28. 28

    Whittall RA et al. (2002) The intron 14 2140+5G>A variant in the low density lipoprotein receptor gene has no effect on plasma cholesterol levels. J Med Genet 39: e57

    CAS  PubMed  PubMed Central  Google Scholar 

  29. 29

    Webb JC et al. (1996) Genetic variation at a splicing branch point in intron 9 of the low density lipoprotein (LDL)-receptor gene: a rare mutation that disrupts mRNA splicing in a patient with familial hypercholesterolaemia and a common polymorphism. Hum Mol Genet 5: 1325–1331

    CAS  PubMed  Google Scholar 

  30. 30

    Graham CA et al. (2005) Genetic screening protocol for familial hypercholesterolemia which includes splicing defects gives an improved mutation detection rate. Atherosclerosis 182: 331–340

    CAS  PubMed  Google Scholar 

  31. 31

    Vega GL and Grundy SM (1986) In vivo evidence for reduced binding of low density lipoproteins to receptors as a cause of primary moderate hypercholesterolemia. J Clin Invest 78: 1410–1414

    CAS  PubMed  PubMed Central  Google Scholar 

  32. 32

    Innerarity TL et al. (1987) Familial defective apolipoprotein B-100: low density lipoproteins with abnormal receptor binding. Proc Natl Acad Sci USA 84: 6919–6923

    CAS  PubMed  Google Scholar 

  33. 33

    Soria LF et al. (1989) Association between a specific apolipoprotein B mutation and familial defective apolipoprotein B-100. Proc Natl Acad Sci USA 86: 587–591

    CAS  PubMed  Google Scholar 

  34. 34

    Arnold KS et al. (1994) Isolation of allele-specific, receptor-binding-defective low density lipoproteins from familial defective apolipoprotein B-100 subjects. J Lipid Res 35: 1469–1476

    CAS  PubMed  Google Scholar 

  35. 35

    Frostegard J et al. (1990) Low density lipoprotein-induced growth of U937 cells: a novel method to determine the receptor binding of low density lipoprotein. J Lipid Res 31: 37–44

    CAS  PubMed  Google Scholar 

  36. 36

    Myant NB (1993) Familial defective apolipoprotein B-100: a review, including some comparisons with familial hypercholesterolaemia. Atherosclerosis 104: 1–18

    CAS  PubMed  Google Scholar 

  37. 37

    Vrablik M et al. (2001) Major apolipoprotein B-100 mutations in lipoprotein metabolism and atherosclerosis. Physiol Res 50: 337–343

    CAS  PubMed  Google Scholar 

  38. 38

    Tybjaerg-Hansen A et al. (1998) Association of mutations in the apolipoprotein B gene with hypercholesterolemia and the risk of ischemic heart disease. N Engl J Med 338: 1577–1584

    CAS  PubMed  Google Scholar 

  39. 39

    Myant NB et al. (1997) Estimation of the age of the ancestral arginine3500→glutamine mutation in human apoB-100. Genomics 45: 78–87

    CAS  PubMed  Google Scholar 

  40. 40

    Teng YN et al. (2000) Familial defective apolipoprotein B-100: detection and haplotype analysis of the Arg(3500) →Gln mutation in hyperlipidemic Chinese. Atherosclerosis 152: 385–390

    CAS  PubMed  Google Scholar 

  41. 41

    Gaffney D et al. (1995) Independent mutations at codon 3500 of the apolipoprotein B gene are associated with hyperlipidemia. Arterioscler Thromb Vasc Biol 15: 1025–1029

    CAS  PubMed  Google Scholar 

  42. 42

    Tai DY et al. (1998) Identification and haplotype analysis of apolipoprotein B-100 Arg3500→Trp mutation in hyperlipidemic Chinese. Clin Chem 44: 1659–1665

    CAS  PubMed  Google Scholar 

  43. 43

    Pullinger CR et al. (1995) Familial ligand-defective apolipoprotein B: identification of a new mutation that decreases LDL receptor binding affinity. J Clin Invest 95: 1225–1234

    CAS  PubMed  PubMed Central  Google Scholar 

  44. 44

    Soutar AK et al. (2003) Genetics, clinical phenotype, and molecular cell biology of autosomal recessive hypercholesterolemia. Arterioscler Thromb Vasc Biol 23: 1963–1970

    CAS  PubMed  Google Scholar 

  45. 45

    Norman D et al. (1999) Characterization of a novel cellular defect in patients with phenotypic homozygous familial hypercholesterolemia. J Clin Invest 104: 619–628

    CAS  PubMed  PubMed Central  Google Scholar 

  46. 46

    Garcia CK et al. (2001) Autosomal recessive hypercholesterolemia caused by mutations in a putative LDL receptor adaptor protein. Science 292: 1394–1398

    CAS  PubMed  Google Scholar 

  47. 47

    Eden ER et al. (2002) Restoration of LDL receptor function in cells from patients with autosomal recessive hypercholesterolemia by retroviral expression of ARH1. J Clin Invest 110: 1695–1702

    CAS  PubMed  PubMed Central  Google Scholar 

  48. 48

    Pisciotta L et al. (2006) Autosomal recessive hypercholesterolemia (ARH) and homozygous familial hypercholesterolemia (FH): a phenotypic comparison. Atherosclerosis 188: 398–405

    CAS  PubMed  Google Scholar 

  49. 49

    Abifadel M et al. (2003) Mutations in PCSK9 cause autosomal dominant hypercholesterolemia. Nat Genet 34: 154–156

    CAS  Google Scholar 

  50. 50

    Leren TP (2004) Mutations in the PCSK9 gene in Norwegian subjects with autosomal dominant hypercholesterolemia. Clin Genet 65: 419–422

    CAS  PubMed  Google Scholar 

  51. 51

    Sun XM et al. (2005) Evidence for effect of mutant PCSK9 on apolipoprotein B secretion as the cause of unusually severe dominant hypercholesterolaemia. Hum Mol Genet 14: 1161–1169

    CAS  PubMed  Google Scholar 

  52. 52

    Timms KM et al. (2004) A mutation in PCSK9 causing autosomal-dominant hypercholesterolemia in a Utah pedigree. Hum Genet 114: 349–353

    CAS  PubMed  Google Scholar 

  53. 53

    Pisciotta L et al. (2006) Additive effect of mutations in LDLR and PCSK9 genes on the phenotype of familial hypercholesterolemia. Atherosclerosis 186: 433–440

    CAS  PubMed  Google Scholar 

  54. 54

    Damgaard D et al. (2004) No genetic linkage or molecular evidence for involvement of the PCSK9, ARH or CYP7A1 genes in the Familial Hypercholesterolemia phenotype in a sample of Danish families without pathogenic mutations in the LDL receptor and apoB genes. Atherosclerosis 177: 415–422

    CAS  PubMed  Google Scholar 

  55. 55

    Horton JD et al. (2003) Combined analysis of oligonucleotide microarray data from transgenic and knockout mice identifies direct SREBP target genes. Proc Natl Acad Sci USA 100: 12027–12032

    CAS  PubMed  Google Scholar 

  56. 56

    Maxwell KN et al. (2003) Novel putative SREBP and LXR target genes identified by microarray analysis in liver of cholesterol-fed mice. J Lipid Res 44: 2109–2119

    CAS  Google Scholar 

  57. 57

    Maxwell KN and Breslow JL (2004) Adenoviral-mediated expression of Pcsk9 in mice results in a low-density lipoprotein receptor knockout phenotype. Proc Natl Acad Sci USA 101: 7100–7105

    PubMed  Google Scholar 

  58. 58

    Park SW et al. (2004) Post-transcriptional regulation of low density lipoprotein receptor protein by proprotein convertase subtilisin/kexin type 9a in mouse liver. J Biol Chem 279: 50630–50638

    CAS  PubMed  Google Scholar 

  59. 59

    Cohen JC et al. (2006) Sequence variations in PCSK9, low LDL, and protection against coronary heart disease. N Engl J Med 354: 1264–1272

    CAS  Google Scholar 

  60. 60

    Ouguerram K et al. (2004) Apolipoprotein B100 metabolism in autosomal-dominant hypercholesterolemia related to mutations in PCSK9. Arterioscler Thromb Vasc Biol 24: 1448–1453

    CAS  PubMed  Google Scholar 

  61. 61

    Kotowski IK et al. (2006) A spectrum of PCSK9 alleles contributes to plasma levels of low-density lipoprotein cholesterol. Am J Hum Genet 78: 410–422

    CAS  PubMed  PubMed Central  Google Scholar 

  62. 62

    Pullinger CR et al. (2002) Human cholesterol 7alpha-hydroxylase (CYP7A1) deficiency has a hypercholesterolemic phenotype. J Clin Invest 110: 109–117

    CAS  PubMed  PubMed Central  Google Scholar 

  63. 63

    Muller PY and Miserez AR (2002) Identification of mutations in the gene encoding sterol regulatory element binding protein (SREBP)-2 in hypercholesterolaemic subjects. J Med Genet 39: 271–275

    CAS  PubMed  PubMed Central  Google Scholar 

  64. 64

    Durst R et al. (2006) The discrete and combined effect of SREBP-2 and SCAP isoforms in the control of plasma lipids among familial hypercholesterolaemia patients. Atherosclerosis 189: 443–450

    CAS  PubMed  Google Scholar 

  65. 65

    Koeijvoets KC et al. (2005) Effect of low-density lipoprotein receptor mutation on lipoproteins and cardiovascular disease risk: a parent-offspring study. Atherosclerosis 180: 93–99

    CAS  PubMed  Google Scholar 

  66. 66

    Koeijvoets KC et al. (2005) Low-density lipoprotein receptor genotype and response to pravastatin in children with familial hypercholesterolemia: substudy of an intima-media thickness trial. Circulation 112: 3168–3173

    CAS  PubMed  Google Scholar 

  67. 67

    Koivisto PV et al. (1993) Deletion of exon 15 of the LDL receptor gene is associated with a mild form of familial hypercholesterolemia: FH-Espoo. Arterioscler Thromb 13: 1680–1688

    CAS  PubMed  Google Scholar 

  68. 68

    Jansen AC et al. (2004) The contribution of classical risk factors to cardiovascular disease in familial hypercholesterolaemia: data in 2400 patients. J Intern Med 256: 482–490

    CAS  PubMed  Google Scholar 

  69. 69

    Pimstone SN et al. (1998) Phenotypic variation in heterozygous familial hypercholesterolemia: a comparison of Chinese patients with the same or similar mutations in the LDL receptor gene in China or Canada. Arterioscler Thromb Vasc Biol 18: 309–315

    CAS  PubMed  Google Scholar 

  70. 70

    Bertolini S et al. (2004) Genetic polymorphisms affecting the phenotypic expression of familial hypercholesterolemia. Atherosclerosis 174: 57–65

    CAS  PubMed  Google Scholar 

  71. 71

    Sato K et al. (2004) Soluble epoxide hydrolase variant (Glu287Arg) modifies plasma total cholesterol and triglyceride phenotype in familial hypercholesterolemia: intrafamilial association study in an eight-generation hyperlipidemic kindred. J Hum Genet 49: 29–34

    CAS  PubMed  PubMed Central  Google Scholar 

  72. 72

    Takada D et al. (2002) Interaction between the LDL-receptor gene bearing a novel mutation and a variant in the apolipoprotein A-II promoter: molecular study in a 1135-member familial hypercholesterolemia kindred. J Hum Genet 47: 656–664

    CAS  PubMed  Google Scholar 

  73. 73

    Takada D et al. (2003) Growth hormone receptor variant (L526I) modifies plasma HDL cholesterol phenotype in familial hypercholesterolemia: intra-familial association study in an eight-generation hyperlipidemic kindred. Am J Med Genet A 121: 136–140

    Google Scholar 

  74. 74

    Jansen AC et al. (2005) Genetic determinants of cardiovascular disease risk in familial hypercholesterolemia. Arterioscler Thromb Vasc Biol 25: 1475–1481

    CAS  PubMed  Google Scholar 

  75. 75

    Karayan L et al. (1994) Response to HMG CoA reductase inhibitors in heterozygous familial hypercholesterolemia due to the 10-kb deletion (“French Canadian mutation”) of the LDL receptor gene. Arterioscler Thromb 14: 1258–1263

    CAS  PubMed  Google Scholar 

  76. 76

    Lind S et al. (2004) Autosomal recessive hypercholesterolaemia: normalization of plasma LDL cholesterol by ezetimibe in combination with statin treatment. J Intern Med 256: 406–412

    CAS  PubMed  Google Scholar 

  77. 77

    Fouchier SW et al. (2005) Update of the molecular basis of familial hypercholesterolemia in The Netherlands. Hum Mutat 26: 550–556

    CAS  PubMed  Google Scholar 

  78. 78

    Humphries SE et al. (2006) Mutational analysis in UK patients with a clinical diagnosis of familial hypercholesterolaemia: relationship with plasma lipid traits, heart disease risk and utility in relative tracing. J Mol Med 84: 203–214

    CAS  PubMed  Google Scholar 

  79. 79

    Tejedor D et al. (2005) Reliable low-density DNA array based on allele-specific probes for detection of 118 mutations causing familial hypercholesterolemia. Clin Chem 51: 1137–1144

    CAS  PubMed  Google Scholar 

  80. 80

    Blesa S et al. (2006) Analysis of sequence variations in the LDL receptor gene in Spain: general gene screening or search for specific alterations? Clin Chem 52: 1021–1025

    CAS  PubMed  Google Scholar 

  81. 81

    Umans-Eckenhausen MA et al. (2001) Review of first 5 years of screening for familial hypercholesterolaemia in the Netherlands. Lancet 357: 165–168

    CAS  PubMed  Google Scholar 

  82. 82

    Leren TP (2004) Cascade genetic screening for familial hypercholesterolemia. Clin Genet 66: 483–487

    CAS  PubMed  Google Scholar 

  83. 83

    Department of Health FH Cascade Testing Audit Project []

  84. 84

    Hadfield SG and Humphries SE (2005) Implementation of cascade testing for the detection of familial hypercholesterolaemia. Curr Opin Lipidol 16: 428–433

    CAS  PubMed  Google Scholar 

  85. 85

    Tonstad S (1996) Familial hypercholesterolaemia: a pilot study of parents' and children's concerns. Acta Paediatr 85: 1307–1313

    CAS  PubMed  Google Scholar 

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Correspondence to Anne K Soutar.

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Soutar, A., Naoumova, R. Mechanisms of Disease: genetic causes of familial hypercholesterolemia. Nat Rev Cardiol 4, 214–225 (2007).

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