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J. Biol. Chem., Vol. 282, Issue 33, 24270-24283, August 17, 2007

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Missense Mutations in APOB within the 1 Domain of Human APOB-100 Result in Impaired Secretion of ApoB and ApoB-containing Lipoproteins in Familial Hypobetalipoproteinemia^*

John R. Burnett¹², Shumei Zhong^¶1, Zhenghui G. Jiang^||1, Amanda J. Hooper, Eric A. Fisher^**, Roger S. McLeod^**, Yang Zhao, P. Hugh R. Barrett, Robert A. Hegele, Frank M. van Bockxmeer^¶¶, Hongyu Zhang^¶, Dennis E. Vance³, C. James McKnight^||4, and Zemin Yao^¶5

From the Department of Core Clinical Pathology and Biochemistry, Royal Perth Hospital and School of Medicine and Pharmacology, University of Western Australia, Perth 6847, Australia, the ^¶Department of Biochemistry, Microbiology, and Immunology, University of Ottawa, Ottawa K1H 8M5, Canada, the ^||Department of Physiology and Biophysics, Boston University School of Medicine, Boston, Massachusetts 02118-2526, the ^**Department of Biochemistry and Molecular Biology, Dalhousie University, Halifax B3H 1X5, Canada, the Department of Biochemistry, University of Alberta, Edmonton T6G 2S2, Canada, Robarts Research Laboratory, London N6A 5K8, Canada, and the ^¶¶School of Surgery and Pathology, University of Western Australia, Perth 6847, Australia

Familial hypobetalipoproteinemia (FHBL) is associated with mutations in the APOB gene. We reported the first missense APOB mutation, R463W, in an FHBL kindred (Burnett, J. R., Shan, J., Miskie, B. A., Whitfield, A. J., Yuan, J., Tran, K., Mc-Knight, C. J., Hegele, R. A., and Yao, Z. (2003) J. Biol. Chem. 278, 13442-13452). Here we identified a second nonsynonymous APOB mutation, L343V, in another FHBL kindred. Heterozygotes for L343V (n = 10) had a mean plasma apoB at 0.31 g/liter as compared with 0.80 g/liter in unaffected family members (n = 22). The L343V mutation impaired secretion of apoB-100 and very low density lipoproteins. The secretion efficiency was 20% for B100wt and 10% for B100LV and B100RW. Decreased secretion of mutant apoB-100 was associated with increased endoplasmic reticulum retention and increased binding to microsomal triglyceride transfer protein and BiP. Reduced secretion efficiency was also observed with B48LV and B17LV. Biochemical and biophysical analyses of apoB domain constructs showed that L343V and R463W altered folding of the -helical domain within the N terminus of apoB. Thus, proper folding of the -helical domain of apoB-100 is essential for efficient secretion.

Received for publication, March 21, 2007 , and in revised form, June 15, 2007.

^* This work was supported by the Heart and Stroke Foundation of Ontario Grant T-4643 (to Z. Y.), National Health and Medical Research Council Grant 403908, National Heart Foundation of Australia Grant G 139 115, the Royal Perth Hospital Medical Research Foundation (to J. R. B., P. H. R. B., and F. m. vB.), American Heart Association Grant 0625943T (to Z. G. J.), National Institutes of Health Grant HL-26335 (to C. J. M.), and Canadian Institutes of Health Research Grants MOP-67073 (to R. S. M.) and MOP-62935 (to D. E. V.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. S1 and S2.

¹ These authors contributed equally to this work.

³ Holds a Canada Research Chair in Molecular and Cell Biology of Lipids and Heritage Scientist of the Alberta Heritage Foundation for Medical Research.

² To whom correspondence may be addressed. Tel.: 61-8-9224-3121; Fax: 61-8-9224-1789; E-mail: john.burnett{at}health.wa.gov.au.

⁴ To whom correspondence may be addressed. Tel.: 617-638-4042; Fax: 617-638-4041; E-mail: cjmck{at}bu.edu.

⁵ Recipient of the Career Investigator Award from Heart and Stroke Foundation of Ontario. To whom correspondence may be addressed. Tel.: 613-562-5800 (ext. 8202); Fax: 613-562-5452; E-mail: zyao{at}uottawa.ca.

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