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J. Biol. Chem., Vol. 278, Issue 15, 13442-13452, April 11, 2003
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From the Familial hypobetalipoproteinemia (FHBL), an
autosomal co-dominant disorder, is associated with reduced plasma
concentrations (<5th percentile for age and sex) of apolipoprotein
(apo) B and
A Novel Nontruncating APOB Gene
Mutation, R463W, Causes Familial Hypobetalipoproteinemia*
§¶,
,,,,
Department of Core Clinical Pathology and
Biochemistry, Royal Perth Hospital and Department of Pathology,
University of Western Australia, Perth WA 6847, Western Australia,
Australia, the Lipoprotein and Atherosclerosis Group, Department
of Pathology and Laboratory Medicine, and Department of Biochemistry,
Microbiology and Immunology, University of Ottawa Heart Institute,
Ottawa, Ontario K1Y 4W7, Canada, the ** Robarts Research
Institute, London, Ontario N6A 5K8, Canada, and the
§§ Department of Physiology and Biophysics,
Boston University School of Medicine,
Boston, Massachusetts 02118-2526
-migrating lipoproteins. To date, only mutations in
APOB encoding prematurely truncated apoB have been found in
FHBL. We discovered a novel APOB gene mutation, namely
R463W, in an extended Christian Lebanese FHBL kindred. Heterozygotes
for R463W had the typical FHBL phenotype, whereas homozygotes had
barely detectable apoB-100. The effect of the R463W mutation on apoB
secretion was examined using transfected McA-RH7777 cells that
expressed one of two recombinant human apoBs, namely B48 and B17. In
both cases, the mutant proteins (B48RW and B17RW) were retained within
the endoplasmic reticulum and were secreted poorly compared with their
wild-type counterparts. Pulse-chase analysis showed that secretion
efficiencies of B48RW and B17RW were, respectively, 45 and 40% lower
than those of the wild-types. Substitution of Arg463 with
Ala in apoB-17 (B17RA) decreased secretion efficiency by ~50%, but
substitution with Lys (B17RK) had no effect on secretion, indicating
that the positive charge was important. Molecular modeling of apoB
predicted that Arg463 was in close proximity to
Glu756 and Asp456. Substitution of
Glu756 with Gln (B17EQ) had no effect on secretion, but
substitution of Asp456 with Asn (B17DN) decreased secretion
to the same extent as B17RW. In co-transfection experiments, the mutant
B17RW showed increased binding to microsomal triglyceride transfer
protein as compared with wild-type B17. Thus, the naturally occurring
R463W mutant reveals a key local domain governing assembly and
secretion of apoB-containing lipoproteins.
*
This work was supported in part by grants from the Royal
Perth Hospital Medical Research Foundation and the Raine Medical Research Foundation (to J. R. B.), National Institutes of
Health Grant HL26335 (to C. J. M.), a Canada Research Chair
(Tier 1) in Human Genetics (to R. A. H.), and a Heart and
Stroke Foundation of Ontario Career Investigator Award (to R. A. H.), grants from the Canadian Genetic Diseases Network,
Canadian Institutes for Health Research Grants MT-13430 and MT-15486,
Heart and Stroke Foundation of Ontario Grants-in-aid T-4643 and T-4772,
and a Scientist Award from the Canadian Institutes for Health Research
(to Z. Y.).The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
Recipient of a John D. Schultz Scholarship from the Heart and
Stroke Foundation of Canada.
¶¶
To whom correspondence may be addressed. Tel.:
519-663-3461; Fax: 519-663-3789; E-mail: hegele@rri.on.ca.
To whom correspondence may be addressed. Tel.:
613-798-5555 (ext. 18711); Fax: 613-761-5281; E-mail:
zyao@ottawaheart.ca.
Copyright © 2003 by The American Society for Biochemistry and Molecular Biology, Inc.
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