title: Molecular mechanisms of autosomal recessive hypercholesterolemia.
abstract: Mutations in the phosphotyrosine-binding domain protein ARH cause autosomal recessive hypercholesterolemia (ARH), an inherited form of hypercholesterolemia due to a tissue-specific defect in the removal of low density lipoproteins (LDL) from the circulation. LDL uptake by the LDL receptor (LDLR) is markedly reduced in the liver but is normal or only moderately impaired in cultured fibroblasts of ARH patients. To define the molecular mechanism underlying ARH we examined ARH mRNA and protein in fibroblasts and lymphocytes from six probands with different ARH mutations. None of the probands had detectable full-length ARH protein in fibroblasts or lymphoblasts. Five probands were homozygous for mutations that introduced premature termination codons. No relationship was apparent between the site of the mutation in ARH and the amount of mRNA. The only mutation identified in the remaining proband was a SINE VNTR Alu (SVA) retroposon insertion in intron 1, which was associated with no detectable ARH mRNA. (125)I-LDL degradation was normal in ARH fibroblasts, as previously reported. In contrast, LDLR function was markedly reduced in ARH lymphoblasts, despite a 2-fold increase in LDL cell surface binding in these cells. These data indicate that all ARH mutations characterized to date preclude the synthesis of full-length ARH and that ARH is required for normal LDLR function in lymphocytes and hepatocytes, but not in fibroblasts. Residual LDLR function in cells that do not require ARH may explain why ARH patients have lower plasma LDL levels than do patients with homozygous familial hypercholesterolemia who have no functional LDLRs.
authors.affiliation: McDermott Center for Human Growth and Development, Department of Molecular Genetics, The Howard Hughes Medical Institute, University of Texas Southwestern Medical Center at Dallas, 5323 Harry Hines Boulevard, Dallas, TX 75390, USA.
authors.forename: Kenneth R
authors.initials: KR
authors.lastname: Wilund
authors.forename: Ming
authors.initials: M
authors.lastname: Yi
authors.forename: Filomena
authors.initials: F
authors.lastname: Campagna
authors.forename: Marcello
authors.initials: M
authors.lastname: Arca
authors.forename: Giovanni
authors.initials: G
authors.lastname: Zuliani
authors.forename: Renato
authors.initials: R
authors.lastname: Fellin
authors.forename: Yiu-Kee
authors.initials: YK
authors.lastname: Ho
authors.forename: J Victor
authors.initials: JV
authors.lastname: Garcia
authors.forename: Helen H
authors.initials: HH
authors.lastname: Hobbs
authors.forename: Jonathan C
authors.initials: JC
authors.lastname: Cohen
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D033942:Adaptor Proteins, Vesicular Transport / Q000235:genetics*; D001483:Base Sequence; D005808:Genes, Recessive; D006801:Humans; D006937:Hypercholesterolemia / Q000235:genetics*; D015151:Immunoblotting; D008214:Lymphocytes; D008969:Molecular Sequence Data; D009154:Mutation
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D033942:Adaptor Proteins, Vesicular Transport; C469745:LDLRAP1 protein, human