Autosomal recessive hypercholesterolemia caused by mutations in a putativeLDL receptor adaptor protein

Atherogenic low density lipoproteins are cleared from the circulation by he patic low density lipoprotein receptors (LDLR). Two inherited forms of hype rcholesterolemia result from loss of LDLR activity: autosomal dominant fami liar hypercholesterolemia (FH), caused by mutations in the LDLR gene, and a utosomal recessive hypercholesterolemia (ARH), of unknown etiology. Here we map the ARH Locus to a similar to1-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 p roteins binds NPXY motifs in the cytoplasmic tails of cell-surface receptor s, including the LDLR. ARH appears to have a tissue-specific role in LDLR f unction, as it is required in liver but not in fibroblasts.