title: Autosomal recessive hypercholesterolemia caused by mutations in a putative LDL receptor adaptor protein.
abstract: Atherogenic low density lipoproteins are cleared from the circulation by hepatic low density lipoprotein receptors (LDLR). Two inherited forms of hypercholesterolemia result from loss of LDLR activity: autosomal dominant familial hypercholesterolemia (FH), caused by mutations in the LDLR gene, and autosomal recessive hypercholesterolemia (ARH), of unknown etiology. Here we map the ARH locus to an approximately 1-centimorgan interval on chromosome 1p35 and identify six mutations in a gene encoding a putative adaptor protein (ARH). ARH contains a phosphotyrosine binding (PTB) domain, which in other proteins binds NPXY motifs in the cytoplasmic tails of cell-surface receptors, including the LDLR. ARH appears to have a tissue-specific role in LDLR function, as it is required in liver but not in fibroblasts.
authors.affiliation: McDermott Center for Human Growth and Development and Department of Internal Medicine, University of Texas Southwestern Medical Center at Dallas, 5323 Harry Hines Boulevard, Dallas, TX 75390, USA.
authors.forename: C K
authors.initials: CK
authors.lastname: Garcia
authors.forename: K
authors.initials: K
authors.lastname: Wilund
authors.forename: M
authors.initials: M
authors.lastname: Arca
authors.forename: G
authors.initials: G
authors.lastname: Zuliani
authors.forename: R
authors.initials: R
authors.lastname: Fellin
authors.forename: M
authors.initials: M
authors.lastname: Maioli
authors.forename: S
authors.initials: S
authors.lastname: Calandra
authors.forename: S
authors.initials: S
authors.lastname: Bertolini
authors.forename: F
authors.initials: F
authors.lastname: Cossu
authors.forename: N
authors.initials: N
authors.lastname: Grishin
authors.forename: R
authors.initials: R
authors.lastname: Barnes
authors.forename: J C
authors.initials: JC
authors.lastname: Cohen
authors.forename: H H
authors.initials: HH
authors.lastname: Hobbs
mesh_terms: D000293:Adolescent; D000328:Adult; D000595:Amino Acid Sequence; D001665:Binding Sites; D002352:Carrier Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D002648:Child; D002675:Child, Preschool; D002874:Chromosome Mapping; D002878:Chromosomes, Human, Pair 1 / Q000235:genetics*; D003001:Cloning, Molecular; D005091:Exons / Q000235:genetics; D005260:Female; D005347:Fibroblasts; D005808:Genes, Recessive / Q000235:genetics*; D006720:Homozygote; D006801:Humans; D006937:Hypercholesterolemia / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D007438:Introns / Q000235:genetics; D007558:Italy; D007861:Lebanon; D008099:Liver / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics*; D009928:Organ Specificity; D010375:Pedigree; D019000:Phosphotyrosine / Q000378:metabolism; D011485:Protein Binding; D012333:RNA, Messenger / Q000032:analysis / Q000235:genetics; D011973:Receptors, LDL / Q000378:metabolism*; D016415:Sequence Alignment; D020798:Two-Hybrid System Techniques
chemical_list: D002352:Carrier Proteins; D012333:RNA, Messenger; D011973:Receptors, LDL; D019000:Phosphotyrosine