Molecular mechanisms of autosomal recessive hypercholesterolemia

Jonathan C. Cohen, Marek Kimmel, Andrzej Polanski, Helen H. Hobbs

Research output: Contribution to journalReview articlepeer-review

51 Scopus citations


Purpose of review: 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. Recent findings: 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 β2-adaptin subunit of AP-2. Summary: The available data suggest that ARH functions as an adaptor protein that couples LDLR to the endocytic machinery.

Original languageEnglish (US)
Pages (from-to)121-127
Number of pages7
JournalCurrent opinion in lipidology
Issue number2
StatePublished - Apr 2003


  • Adaptor protein
  • Clathrin-box
  • Endocytosis
  • Low density lipoprotein receptor
  • Phosphotyrosine binding domain

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Molecular Biology
  • Genetics
  • Nutrition and Dietetics
  • Cardiology and Cardiovascular Medicine
  • Cell Biology


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