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Human Molecular Genetics Advance Access originally published online on August 29, 2007
Human Molecular Genetics 2007 16(22):2751-2759; doi:10.1093/hmg/ddm232
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© 2007 The Author(s)
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.0/uk/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Adaptor protein Disabled-2 modulates low density lipoprotein receptor synthesis in fibroblasts from patients with autosomal recessive hypercholesterolaemia

Emily R. Eden{dagger},{ddagger}, Xi-Ming Sun{ddagger}, Dilipkumar D. Patel and Anne K. Soutar*

MRC Clinical Sciences Centre, Imperial College London, Hammersmith Hospital, DuCane Road, London W12 ONN, UK

* To whom correspondence shoud be addressed. Tel: +44 2083832324; Fax: +44 2083832077; Email: anne.soutar{at}csc.mrc.ac.uk

Revised August 14, 2007; Accepted August 19, 2007

Autosomal recessive hypercholesterolaemia (ARH), characterized clinically by severe inherited hypercholesterolaemia, is caused by recessive null mutations in LDLRAP1 (formerly ARH). Immortalized lymphocytes and monocyte-macrophages, and presumably hepatocytes, from ARH patients fail to take up and degrade plasma low density lipoproteins (LDL) because they lack LDLRAP1, a cargo-specific adaptor required for clathrin-mediated endocytosis of the LDL receptor. Surprisingly, LDL-receptor function is normal in ARH patients' skin fibroblasts in culture. Disabled-2 (Dab2) has been implicated previously in clathrin-mediated internalization of LDL-receptor family members, and we show here that Dab2 is highly expressed in skin fibroblasts, but not in lymphocytes. SiRNA-depletion of Dab2 profoundly reduced LDL-receptor activity in ARH fibroblasts as a result of profound reduction in LDL-receptor protein, but not mRNA; heterologous expression of murine Dab2 reversed this effect. In contrast, LDL-receptor protein content was unchanged in Dab-2-depleted control cells. Incorporation of 35S-labelled amino acids into LDL receptor protein revealed a corresponding apparent reduction in accumulation of newly synthesized LDL-receptor protein on depletion of Dab2 in ARH, but not in control, cells. This reduction in LDL-receptor protein in Dab2-depleted ARH cells could not be reversed by treatment of the cells with proteasomal or lysosomal inhibitors. Thus, we propose a novel role for Dab2 in ARH fibroblasts, where it is apparently required to allow normal translation of LDL receptor mRNA.

{ddagger} The authors wish it to be known that, in their opinion, the first two authors should be regarded as joint First Authors.

{dagger} Present address: Cell Biology, Institute of Ophthalmology, 11-43 Bath Street, London EC1V 9EL, UK.


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