title: Molecular mechanisms of autosomal recessive hypercholesterolemia.
abstract: OBJECTIVE
  Autosomal recessive hypercholesterolemia (ARH) is a rare Mendelian dyslipidemia characterized by markedly elevated plasma LDL levels, xanthomatosis, and premature coronary artery disease. LDL receptor function is normal, or only moderately impaired in fibroblasts from ARH patients, but their cultured lymphocytes show increased cell-surface LDL binding, and impaired LDL degradation, consistent with a defect in LDL receptor internalization. Recently, the disorder was shown to be caused by mutations in a phosphotyrosine binding domain protein, ARH, which is required for internalization of low density lipoproteins in the liver. This review summarizes the findings of new investigations into the pathophysiology and molecular genetics of ARH.
  
  
  RESULTS
  All mutations that have been characterized to date preclude the synthesis of a full-length protein. GST-pulldown experiments indicate that the phosphotyrosine binding domain of ARH interacts with the internalization sequence (NPVY) in the cytoplasmic tail of LDLR, and that conserved motifs in the C-terminal portion of the protein bind to clathrin and to the beta2-adaptin subunit of AP-2.
  
  
  CONCLUSIONS
  The available data suggest that ARH functions as an adaptor protein that couples LDLR to the endocytic machinery.
authors.affiliation: McDermott Center for Human Growth and Development, Center for Human Nutrition, Department of Internal Medicine, The Howard Hughes Medical Institute, University of Texas Southwestern Medical Center at Dallas, USA. jonathan.cohen@utsouthwestern.edu
authors.forename: Jonathan C
authors.initials: JC
authors.lastname: Cohen
authors.forename: Marek
authors.initials: M
authors.lastname: Kimmel
authors.forename: Andrzej
authors.initials: A
authors.lastname: Polanski
authors.forename: Helen H
authors.initials: HH
authors.lastname: Hobbs
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D033942:Adaptor Proteins, Vesicular Transport / Q000737:chemistry; D000595:Amino Acid Sequence; D000818:Animals; D005808:Genes, Recessive / Q000235:genetics*; D005828:Genetics, Population; D006801:Humans; D006937:Hypercholesterolemia / Q000235:genetics* / Q000378:metabolism*; D008969:Molecular Sequence Data; D011973:Receptors, LDL / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D033942:Adaptor Proteins, Vesicular Transport; C469745:LDLRAP1 protein, human; D011973:Receptors, LDL