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Originally published in Science Express on 26 April 2001
Science 18 May 2001:
Vol. 292. no. 5520, pp. 1394 - 1398
DOI: 10.1126/science.1060458
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Reports

Autosomal Recessive Hypercholesterolemia Caused by Mutations in a Putative LDL Receptor Adaptor Protein

Christine Kim Garcia,1 Kenneth Wilund,12 Marcello Arca,3 Giovanni Zuliani,4 Renato Fellin,4 Mario Maioli,5 Sebastiano Calandra,6 Stefano Bertolini,7 Fausto Cossu,8 Nick Grishin,9 Robert Barnes,1 Jonathan C. Cohen,1 Helen H. Hobbs12*

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 a ~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.

1 McDermott Center for Human Growth and Development and Department of Internal Medicine and
2 Molecular Genetics,
9 Howard Hughes Medical Institute and Department of Biochemistry, University of Texas Southwestern Medical Center at Dallas, 5323 Harry Hines Boulevard, Dallas, TX 75390, USA.
3 Institute of Systematic Medical Therapy, University of Rome "La Sapienza," Rome 00161, Italy.
4 Department of Internal Medicine, University of Ferrara, Ferrara 44100, Italy.
5 Metabolic Disease Unit, Department of Internal Medicine, University of Sassari, Sassari 07100, Italy.
6 Department of Biological Science, University of Modena and Reggioemilia, Modena 41100, Italy.
7 Department of Internal Medicine, University of Genoa, Genoa 16100, Italy.
8 Bone Marrow Transplant Unit, Ospedale Microcitemico, Cagliari 09121, Italy.
*   To whom correspondence should be addressed. Email: helen.hobbs{at}UTSouthwestern.edu

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