This Article Full Text Full Text (PDF) All Versions of this Article: 23/11/1963    most recent 01.ATV.0000094410.66558.9Av1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Soutar, A. K. Articles by Traub, L. M. Search for Related Content PubMed PubMed Citation Articles by Soutar, A. K. Articles by Traub, L. M. Related Collections Lipid and lipoprotein metabolism

(Arteriosclerosis, Thrombosis, and Vascular Biology. 2003;23:1963.)
© 2003 American Heart Association, Inc.

Brief Reviews

Genetics, Clinical Phenotype, and Molecular Cell Biology of Autosomal Recessive Hypercholesterolemia

Anne K. Soutar; Rossitza P. Naoumova; Linton M. Traub

From the Medical Research Council Clinical Sciences Centre (A.K.S., R.P.N.), Faculty of Medicine, Imperial College, London, UK, and the Department of Cell Biology and Physiology (L.M.T.), University of Pittsburgh School of Medicine, Pittsburgh, Pa.

Correspondence to Anne K. Soutar, MRC Clinical Sciences Centre, Hammersmith Hospital, Ducane Road, London W12 0NN, UK. E-mail anne.soutar{at}csc.mrc.ac.uk

The recent characterization of a rare genetic defect causing autosomal recessive hypercholesterolemia (ARH) has provided new insights into the underlying mechanism of clathrin-mediated internalization of the LDL receptor. Mutations in ARH on chromosome 1p35-36.1 prevent normal internalization of the LDL receptor by cultured lymphocytes and monocyte-derived macrophages but not by skin fibroblasts. In affected cells, LDL receptor protein accumulates at the cell surface; this also occurs in the livers of recombinant mice lacking ARH, thereby providing an explanation for the failure of clearance of LDL from the plasma in subjects lacking ARH. The 50 known affected individuals are mostly of Sardinian or Middle Eastern origin. The clinical phenotype of ARH is similar to that of classic homozygous familial hypercholesterolemia caused by defects in the LDL receptor gene, but it is more variable, generally less severe, and more responsive to lipid-lowering therapy. Structural features of the ARH protein and its capacity to interact simultaneously with the internalization sequence of the LDL receptor, plasma membrane phospholipids, and the clathrin endocytic machinery suggest how ARH can play a pivotal role in gathering the LDL receptor into forming endocytic carrier vesicles.

Key Words: lipids • adaptor • clathrin • clinical phenotype • endocytosis • LDL receptor

This article has been cited by other articles:

				E. R. Eden, X.-M. Sun, D. D. Patel, and A. K. Soutar Adaptor protein Disabled-2 modulates low density lipoprotein receptor synthesis in fibroblasts from patients with autosomal recessive hypercholesterolaemia Hum. Mol. Genet., November 15, 2007; 16(22): 2751 - 2759. [Abstract] [Full Text] [PDF]

				E. Ikonen Mechanisms for cellular cholesterol transport: defects and human disease. Physiol Rev, October 1, 2006; 86(4): 1237 - 1261. [Abstract] [Full Text] [PDF]

				S. K. Mishra, P. A. Keyel, M. A. Edeling, A. L. Dupin, D. J. Owen, and L. M. Traub Functional Dissection of an AP-2 {beta}2 Appendage-binding Sequence within the Autosomal Recessive Hypercholesterolemia Protein J. Biol. Chem., May 13, 2005; 280(19): 19270 - 19280. [Abstract] [Full Text] [PDF]

				X.-M. Sun, E. R. Eden, I. Tosi, C. K. Neuwirth, D. Wile, R. P. Naoumova, and A. K. Soutar Evidence for effect of mutant PCSK9 on apolipoprotein B secretion as the cause of unusually severe dominant hypercholesterolaemia Hum. Mol. Genet., May 1, 2005; 14(9): 1161 - 1169. [Abstract] [Full Text] [PDF]

				K. N. Maxwell, E. A. Fisher, and J. L. Breslow Overexpression of PCSK9 accelerates the degradation of the LDLR in a post-endoplasmic reticulum compartment PNAS, February 8, 2005; 102(6): 2069 - 2074. [Abstract] [Full Text] [PDF]

				M. A. Austin, C. M. Hutter, R. L. Zimmern, and S. E. Humphries Genetic Causes of Monogenic Heterozygous Familial Hypercholesterolemia: A HuGE Prevalence Review Am. J. Epidemiol., September 1, 2004; 160(5): 407 - 420. [Abstract] [Full Text] [PDF]

				P. Michaely, W.-P. Li, R. G. W. Anderson, J. C. Cohen, and H. H. Hobbs The Modular Adaptor Protein ARH Is Required for Low Density Lipoprotein (LDL) Binding and Internalization but Not for LDL Receptor Clustering in Coated Pits J. Biol. Chem., August 6, 2004; 279(32): 34023 - 34031. [Abstract] [Full Text] [PDF]

				P. M. Smith, A. Cowan, and B. A. White The Low-Density Lipoprotein Receptor Is Regulated by Estrogen and Forms a Functional Complex with the Estrogen-Regulated Protein Ezrin in Pituitary GH3 Somatolactotropes Endocrinology, July 1, 2004; 145(7): 3075 - 3083. [Abstract] [Full Text] [PDF]