48 Citations (Scopus)

Abstract

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
Volume14
Issue number2
DOIs
StatePublished - Apr 2003

Fingerprint

Phosphotyrosine
LDL Receptors
Proteins
Clathrin
Lymphocytes
Fibroblasts
LDL Lipoproteins
Liver
Machinery
Xanthomatosis
Mutation
Dyslipidemias
Plasmas
Degradation
Defects
Autosomal Recessive Hypercholesterolemia
Coronary Artery Disease
Molecular Biology
Carrier Proteins
oxidized low density lipoprotein

Keywords

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

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Molecular mechanisms of autosomal recessive hypercholesterolemia. / Cohen, Jonathan C.; Kimmel, Marek; Polanski, Andrzej; Hobbs, Helen H.

In: Current Opinion in Lipidology, Vol. 14, No. 2, 04.2003, p. 121-127.

Research output: Contribution to journalArticle

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