Autosomal Recessive Hypercholesterolemia

ABSTRACT

Autosomal recessive hypercholesterolemia (ARH) presents with a clinical phenotype similar to that of classical homozygous familial hypercholesterolemia (FH) caused by defects in the low-density lipoprotein (LDL) receptor gene but is more variable, generally less severe, and more responsive to lipid-lowering therapy than homozygous FH; furthermore, FH is inherited with a dominant pattern. The ∼50 known affected ARH individuals are mostly of Sardinian or Middle Eastern origin, but rare cases of ARH have occurred worldwide. The physiological defect in ARH is a failure of some, but not all, cell types to mediate LDL receptor-dependent internalization of LDL and is caused by mutations in the gene for a putative adaptor protein called ARH. In affected cells, the LDL receptor gene is normal but LDL receptor protein accumulates at the cell surface; this also occurs in livers of recombinant mice lacking ARH, providing an explanation for the failure of clearance of LDL from plasma in ARH patients. The structural features of the ARH protein and its capacity to interact with the internalization sequence of the LDL receptor, plasma membrane phospholipids, and the clathrin endocytic machinery suggest that it plays a key role in the LDL receptor pathway.

Xanthoma - LDL-receptor pathway - genetic disorder - lipoprotein metabolism - premature coronary disease - aortic valve

REFERENCES

• 1 Goldstein J, Hobbs H, Brown M. Familial hypercholesterolemia. In: Valle D, Scriver CR, Beaudet A, Sly WS, Childs B, Kinzler KW, et al The Metabolic and Molecular Bases of Inherited Disease New York; McGraw-Hill 2001: 2863-2913
• 2 Miserez A R, Keller U. Differences in the phenotypic characteristics of subjects with familial defective apolipoprotein B-100 and familial hypercholesterolemia.  Arterioscler Thromb Vasc Biol. 1995;  15 1719-1729
• 3 Khachadurian A K. The inheritance of essential familial hypercholesterolemia.  Am J Med. 1964;  37 402-407
• 4 Khachadurian A K, Uthman S M. Experiences with the homozygous cases of familial hypercholesterolemia. A report of 52 patients.  Nutr Metab. 1973;  15 132-140
• 5 Harada-Shiba M, Tajima S, Yokoyama S et al.. Siblings with normal LDL-receptor activity and severe hypercholesterolemia.  Arterioscler Thromb. 1992;  12 1071-1078
• 6 Zuliani G, Arca M, Signore A et al.. Characterization of a new form of inherited hypercholesterolemia: familial recessive hypercholesterolemia.  Arterioscler Thromb Vasc Biol. 1999;  19 802-809
• 7 Schmidt H H, Stuhrmann M, Shamburek R et al.. Delayed low density lipoprotein (LDL) catabolism despite a functional intact LDL-apolipoprotein B particle and LDL-receptor in a subject with clinical homozygous familial hypercholesterolemia.  J Clin Endocrinol Metab. 1998;  83 2167-2174
• 8 Norman D, Sun X M, Bourbon M, Knight B L, Naoumova R P, Soutar A K. Characterization of a novel cellular defect in patients with phenotypic homozygous familial hypercholesterolemia.  J Clin Invest. 1999;  104 619-628
• 9 Bourbon M, Fowler A M, Sun X M, Soutar A K. Inheritance of two different alleles of the low-density lipoprotein (LDL)-receptor gene carrying the recurrent Pro664Leu mutation in a patient with homozygous familial hypercholesterolaemia.  Clin Genet. 1999;  56 225-231
• 10 Eden E R, Naoumova R P, Burden J J, McCarthy M I, Soutar A K. Use of homozygosity mapping to identify a region on chromosome 1 bearing a defective gene that causes autosomal recessive homozygous hypercholesterolemia in two unrelated families.  Am J Hum Genet. 2001;  68 653-660
• 11 Garcia C K, Wilund K, Arca M et al.. Autosomal recessive hypercholesterolemia caused by mutations in a putative LDL receptor adaptor protein.  Science. 2001;  292 1394-1398
• 12 Eden E R, Patel D D, Sun X M et al.. Restoration of LDL-receptor function in cells from patients with autosomal recessive hypercholesterolemia by retroviral expression of ARH1.  J Clin Invest. 2002;  110 1695-1702
• 13 Wilund K R, Yi M, Campagna F et al.. Molecular mechanisms of autosomal recessive hypercholesterolemia.  Hum Mol Genet. 2002;  11 3019-3030
• 14 Arca M, Zuliani G, Wilund K et al.. Autosomal recessive hypercholesterolaemia in Sardinia, Italy, and mutations in ARH: a clinical and molecular genetic analysis.  Lancet. 2002;  359 841-847
• 15 Barbagallo C M, Emmanuele G, Cefalu A B et al.. Autosomal recessive hypercholesterolemia in a Sicilian kindred harboring the 432insA mutation of the ARH gene.  Atherosclerosis. 2003;  166 395-400
• 16 Naoumova R P, Neuwirth C, Lee P, Miller J P, Taylor K G, Soutar A K. Autosomal recessive hypercholesterolaemia: long-term follow up and response to treatment.  Atherosclerosis. 2004;  174 165-172
• 17 Harada-Shiba M, Takagi A, Miyamoto Y et al.. Clinical features and genetic analysis of autosomal recessive hypercholesterolemia.  J Clin Endocrinol Metab. 2003;  88 2541-2547
• 18 Tietge U J, Genschel J, Schmidt H H. A Q136Stop mutation in the ARH gene causing autosomal recessive hypercholesterolaemia with severely delayed LDL catabolism.  J Intern Med. 2003;  253 582-583
• 19 Al Kateb H, Bahring S, Hoffmann K et al.. Mutation in the ARH gene and a chromosome 13q locus influence cholesterol levels in a new form of digenic-recessive familial hypercholesterolemia.  Circ Res. 2002;  90 951-958
• 20 Jones C, Hammer R E, Li W P, Cohen J C, Hobbs H H, Herz J. Normal sorting, but defective endocytosis of the LDL receptor in mice with autosomal recessive hypercholesterolemia.  J Biol Chem. 2003;  278 29024-29030
• 21 Chen W J, Goldstein J L, Brown M S. NPXY, a sequence often found in cytoplasmic tails, is required for coated pit-mediated internalization of the low density lipoprotein receptor.  J Biol Chem. 1990;  265 3116-3123
• 22 Davis C G, Lehrman M A, Russell D W, Anderson R G, Brown M S, Goldstein J L. The J.D. mutation in familial hypercholesterolemia: amino acid substitution in cytoplasmic domain impedes internalization of LDL receptors.  Cell. 1986;  45 15-24
• 23 Bonifacino J S, Traub L M. Signals for sorting of transmembrane proteins to endosomes and lysosomes.  Annu Rev Biochem. 2003;  72 395-447
• 24 Warren R A, Green F A, Stenberg P E, Enns C A. Distinct saturable pathways for the endocytosis of different tyrosine motifs.  J Biol Chem. 1998;  273 17056-17063
• 25 He G, Gupta S, Yi M, Michaely P, Hobbs H H, Cohen J C. ARH is a modular adaptor protein that interacts with the LDL receptor, clathrin, and AP-2.  J Biol Chem. 2002;  277 44044-44049
• 26 Mishra S K, Keyel P A, Hawryluk M J, Agostinelli N R, Watkins S C, Traub L M. Disabled-2 exhibits the properties of a cargo-selective endocytic clathrin adaptor.  EMBO J. 2002;  21 4915-4926
• 27 Zhou Y, Zhang J, King M L. Xenopus autosomal recessive hypercholesterolemia protein couples lipoprotein receptors with the AP-2 complex in oocytes and embryos and is required for vitellogenesis.  J Biol Chem. 2003;  278 44584-44592
• 28 Noviello C, Vito P, Lopez P, Abdallah M, D'Adamio L. Autosomal recessive hypercholesterolemia protein interacts with and regulates the cell surface level of Alzheimer's amyloid b precursor protein.  J Biol Chem. 2003;  278 31843-31847
• 29 Nagai M, Meerloo T, Takeda T, Farquhar M G. The adaptor protein ARH escorts megalin to and through endosomes.  Mol Biol Cell. 2003;  14 4984-4996
• 30 Cohen J C, Kimmel M, Polanski A, Hobbs H H. Molecular mechanisms of autosomal recessive hypercholesterolemia.  Curr Opin Lipidol. 2003;  14 121-127
• 31 Thompson G R. A Handbook of Hyperlipidaemia. 2nd ed. London; Current Science 1994
• 32 Zuliani G, Vigna G B, Corsini A, Maioli M, Romagnoni F, Fellin R. Severe hypercholesterolaemia: unusual inheritance in an Italian pedigree.  Eur J Clin Invest. 1995;  25 322-331