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(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

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