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

ABSTRACT—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 internalizati...

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Published inArteriosclerosis, thrombosis, and vascular biology Vol. 23; no. 11; pp. 1963 - 1970
Main Authors Soutar, Anne K., Naoumova, Rossitza P., Traub, Linton M.
Format Journal Article
LanguageEnglish
Published Philadelphia, PA American Heart Association, Inc 01.11.2003
Hagerstown, MD Lippincott
Subjects
Online AccessGet full text
ISSN1079-5642
1524-4636
1524-4636
DOI10.1161/01.ATV.0000094410.66558.9A

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Abstract ABSTRACT—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.
AbstractList 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 approximately 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.
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.
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 approximately 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.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 approximately 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.
ABSTRACT—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.
Author Naoumova, Rossitza P.
Soutar, Anne K.
Traub, Linton M.
AuthorAffiliation 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
AuthorAffiliation_xml – name: 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
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  givenname: Anne
  surname: Soutar
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  fullname: Soutar, Anne K.
  organization: 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
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Issue 11
Keywords Human
Clathrin
Pathogenesis
Metabolic diseases
Genotype
Lipids
adaptor
Hyperlipoproteinemia
Autosome
Hereditary
Genetic determinism
LDL receptor
clinical phenotype
Lipoprotein LDL
Phenotype
Hypercholesterolemia
endocytosis
Dyslipemia
Molecular biology
Recession
Biological receptor
Language English
License CC BY 4.0
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PublicationTitle Arteriosclerosis, thrombosis, and vascular biology
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Lippincott
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Snippet ABSTRACT—The recent characterization of a rare genetic defect causing autosomal recessive hypercholesterolemia (ARH) has provided new insights into the...
The recent characterization of a rare genetic defect causing autosomal recessive hypercholesterolemia (ARH) has provided new insights into the underlying...
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SubjectTerms Biological and medical sciences
Cholesterol, LDL - metabolism
Clathrin - metabolism
Disorders of blood lipids. Hyperlipoproteinemia
Endocytosis - physiology
Genetic Variation
Humans
Hyperlipoproteinemia Type II - genetics
Hyperlipoproteinemia Type II - metabolism
Hyperlipoproteinemia Type II - therapy
Hypolipidemic Agents - therapeutic use
Medical sciences
Metabolic diseases
Mutation
Phenotype
Receptors, LDL - metabolism
Title Genetics, Clinical Phenotype, and Molecular Cell Biology of Autosomal Recessive Hypercholesterolemia
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https://www.ncbi.nlm.nih.gov/pubmed/12958046
https://www.proquest.com/docview/204285002
https://www.proquest.com/docview/71374584
Volume 23
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