A Novel Nontruncating APOB Gene Mutation, R463W, Causes Familial Hypobetalipoproteinemia*

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 β-migrating lipoproteins. To date, only mutations inAPOB 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.

• Publication year

  2003

• Venue

  Journal of Biological Chemistry

• Publication date

  2003-04-11

• Fields of study

  Biology, Medicine

• Identifiers
  DOI 10.1074/JBC.M300235200PMID 12551903
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

• Intracellular Assembly of Very Low Density Lipoproteins Containing Apolipoprotein B100 in Rat Hepatoma McA-RH7777 Cells*

  2002cited by this paper
• The Metabolic and Molecular Bases of Inherited Disease

  2001cited by this paper
• Structure of apolipoprotein B-100 in low density lipoproteins.

  2001cited by this paper
• The N-terminal 17% of apoB binds tightly and irreversibly to emulsions modeling nascent very low density lipoproteins.

  2001cited by this paper
• Monogenic dyslipidemias: window on determinants of plasma lipoprotein metabolism.

  2001cited by this paper
• Phenotypic expression of familial hypobetalipoproteinemia in three kindreds with mutations of apolipoprotein B gene.

  2001cited by this paper
• Physical Proximity and Functional Association of Glycoprotein 1bα and Protein-disulfide Isomerase on the Platelet Plasma Membrane*

  2000cited by this paper
• The Assembly and Secretion of Apolipoprotein B-48-containing Very Low Density Lipoproteins in McA-RH7777 Cells*

  2000cited by this paper
• Disulfide Bonds Are Required for Folding and Secretion of Apolipoprotein B Regardless of Its Lipidation State*

  2000cited by this paper
• A study of fatty liver disease and plasma lipoproteins in a kindred with familial hypobetalipoproteinemia due to a novel truncated form of apolipoprotein B (APO B-54.5).

  2000cited by this paper
• Interdependence of serum concentrations of vitamin K1, vitamin E, lipids, apolipoprotein A1, and apolipoprotein B: importance in assessing vitamin status.

  1999cited by this paper
• N-terminal domain of apolipoprotein B has structural homology to lipovitellin and microsomal triglyceride transfer protein: a "lipid pocket" model for self-assembly of apob-containing lipoprotein particles.

  1999cited by this paper
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  1999cited by this paper
• The structure of vitellogenin provides a molecular model for the assembly and secretion of atherogenic lipoproteins.

  1999cited by this paper
• Decreased production rates of VLDL triglycerides and ApoB-100 in subjects heterozygous for familial hypobetalipoproteinemia.

  1999cited by this paper
• A Common Binding Site on the Microsomal Triglyceride Transfer Protein for Apolipoprotein B and Protein Disulfide Isomerase*

  1999cited by this paper
• Amino Acids 430–570 in Apolipoprotein B Are Critical for Its Binding to Microsomal Triglyceride Transfer Protein*

  1998cited by this paper
• Functional Analysis of Disulfide Linkages Clustered within the Amino Terminus of Human Apolipoprotein B*

  1998cited by this paper
• Genetic heterogeneity in familial hypobetalipoproteinemia: linkage and non-linkage to the apoB gene in Caucasian families.

  1998cited by this paper
• Lysine and arginine residues in the N-terminal 18% of apolipoprotein B are critical for its binding to microsomal triglyceride transfer protein.

  1998cited by this paper
• The structural basis of lipid interactions in lipovitellin, a soluble lipoprotein.

  1998cited by this paper
• Fatty liver in a case with heterozygous familial hypobetalipoproteinemia.

  1997cited by this paper
• Apolipoprotein B binding to microsomal triglyceride transfer protein decreases with increases in length and lipidation: implications in lipoprotein biosynthesis.

  1997cited by this paper
• Identification of Cysteine Pairs within the Amino-terminal 5% of Apolipoprotein B Essential for Hepatic Lipoprotein Assembly and Secretion*

  1997cited by this paper
• Intracellular degradation of newly synthesized apolipoprotein B.

  1997cited by this paper
• Decreased production and increased catabolism of apolipoprotein B-100 in apolipoprotein B-67/B-100 heterozygotes.

  1997cited by this paper
• The Microsomal Triglyceride Transfer Protein Facilitates Assembly and Secretion of Apolipoprotein B-containing Lipoproteins and Decreases Cotranslational Degradation of Apolipoprotein B in Transfected COS-7 Cells*

  1996cited by this paper
• The Amino Terminus of Apolipoprotein B Is Necessary but Not Sufficient for Microsomal Triglyceride Transfer Protein Responsiveness (*)

  1996cited by this paper
• Homozygous familial hypobetalipoproteinemia. Increased LDL catabolism in hypobetalipoproteinemia due to a truncated apolipoprotein B species, apo B-87Padova.

  1996cited by this paper
• Apolipoprotein B Sequence Requirements for Hepatic Very Low Density Lipoprotein Assembly

  1996cited by this paper
• Positive linear correlation between the length of truncated apolipoprotein B and its secretion rate: in vivo studies in human apoB-89, apoB-75, apoB-54.8, and apoB-31 heterozygotes.

  1996cited by this paper
• MOLMOL: a program for display and analysis of macromolecular structures.

  1996cited by this paper
• Apoprotein B-100 production is decreased in subjects heterozygous for truncations of apoprotein B.

  1995cited by this paper
• Characterization of recombinant human apoB-48-containing lipoproteins in rat hepatoma McA-RH7777 cells transfected with apoB-48 cDNA. Overexpression of apoB-48 decreases synthesis of endogenous apoB-100.

  1995cited by this paper
• Synthesis and secretion of hepatic apolipoprotein B-containing lipoproteins.

  1994cited by this paper
• Carboxyl-terminal truncation impairs lipid recruitment by apolipoprotein B100 but does not affect secretion of the truncated apolipoprotein B-containing lipoproteins.

  1994cited by this paper
• Cloning and gene defects in microsomal triglyceride transfer protein associated with abetalipoproteinaemia

  1993cited by this paper
• Comparative protein modelling by satisfaction of spatial restraints.

  1993cited by this paper
• Familial hypobetalipoproteinemia.

  1993cited by this paper
• Familial hypobetalipoproteinaemia: a rare presentation to the lipid clinic

  1993cited by this paper
• Apolipoprotein B, the major protein component of triglyceride-rich and low density lipoproteins.

  1992cited by this paper
• Sequence of lamprey vitellogenin. Implications for the lipovitellin crystal structure.

  1992cited by this paper
• Lipoprotein assembly. Apolipoprotein B size determines lipoprotein core circumference.

  1992cited by this paper
• Apolipoprotein B-32: a new truncated mutant of human apolipoprotein B capable of forming particles in the low density lipoprotein range.

  1992cited by this paper
• Lipoproteins containing the truncated apolipoprotein, Apo B-89, are cleared from human plasma more rapidly than Apo B-100-containing lipoproteins in vivo.

  1992cited by this paper
• Expression of carboxyl-terminally truncated forms of human apolipoprotein B in rat hepatoma cells. Evidence that the length of apolipoprotein B has a major effect on the buoyant density of the secreted lipoproteins.

  1991cited by this paper
• Carboxyl-terminal truncation of apolipoprotein B results in gradual loss of the ability to form buoyant lipoproteins in cultured human and rat liver cell lines.

  1991cited by this paper
• Restriction isotyping of human apolipoprotein E by gene amplification and cleavage with HhaI.

  1990cited by this paper
• Recent Progress in Understanding Apolipoprotein B

  1990cited by this paper
• Basic local alignment search tool.

  1990cited by this paper
• An expression system for human apolipoprotein B100 in a rat hepatoma cell line.

  1990cited by this paper
• Plasma very low density lipoproteins contain a single molecule of apolipoprotein B.

  1988cited by this paper
• Apolipoprotein B-48 is the product of a messenger RNA with an organ-specific in-frame stop codon.

  1987cited by this paper
• Complete protein sequence and identification of structural domains of human apolipoprotein B

  1986cited by this paper
• Structure of the human apolipoprotein B gene.

  1986cited by this paper
• The complete sequence and structural analysis of human apolipoprotein B‐100: relationship between apoB‐100 and apoB‐48 forms.

  1986cited by this paper
• Nycodenz: a new nonionic iodinated gradient medium.

  1982cited by this paper

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  2026cites this paper
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  2025cites this paper
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  2023cites this paper
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  2022cites this paper
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  2022cites this paper
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  2020cites this paper
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  2019cites this paper
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  2019cites this paper
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  2019cites this paper
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  2016cites this paper
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  2016cites this paper
• Update on the molecular biology of dyslipidemias.

  2016cites this paper
• Phenotypic variability in 4 homozygous familial hypercholesterolemia siblings compound heterozygous for LDLR mutations.

  2016cites this paper
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  2016cites this paper
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  2016cites this paper
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  2015cites this paper
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  2013cites this paper
• [Research progress in heritable dyslipidemia].

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  2013cites this paper
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  2010cites this paper
• [Genetic analysis of epistatic effects between ApoB and UCP on abdominal fat trait in chicken].

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  2010cites this paper
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  2009cites this paper
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  2009cites this paper
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  2009cites this paper
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  2009cites this paper
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  2009cites this paper
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  2009cites this paper
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  2009cites this paper
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  2008cites this paper
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  2008cites this paper
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  2008cites this paper
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  2008cites this paper
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  2008cites this paper
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  2008cites this paper
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  2008cites this paper
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  2007cites this paper
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  2007cites this paper
• Genetics of familial hypobetalipoproteinemia

  2007cites this paper
• Postprandial lipoprotein metabolism in familial hypobetalipoproteinemia.

  2007cites this paper
• Novel mutations in abetalipoproteinaemia and homozygous familial hypobetalipoproteinaemia

  2007cites this paper
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  2007cites this paper
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  2007cites this paper
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  2006cites this paper
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  2006cites this paper
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  2006cites this paper
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  2006cites this paper
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  2005cites this paper
• Contribution de l'intestin dans le syndrome de résistance à l'insuline chez l'enfant

  2005cites this paper
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  2005cites this paper
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  2005cites this paper
• Absence of fatty liver in familial hypobetalipoproteinemia linked to chromosome 3p21.

  2005cites this paper
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  2005cites this paper
• Familial hypobetalipoproteinemia: genetics and metabolism

  2005cites this paper
• Hepatic and Cardiovascular Consequences of Familial Hypobetalipoproteinemia

  2005cites this paper
• Monogenic Hypocholesterolaemic Lipid Disorders and Apolipoprotein B Metabolism

  2005cites this paper
• Liver dysfunction and steatosis in familial hypobetalipoproteinemia.

  2005cites this paper
• Lipid disorders and mutations in the APOB gene.

  2004cites this paper
• The genes and proteins of atherogenic lipoprotein production.

  2004cites this paper
• Hypobetalipoproteinemia with an apparently recessive inheritance due to a "de novo" mutation of apolipoprotein B.

  2004cites this paper
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  2003cites this paper
• Familial hypobetalipoproteinemia Published, JLR Papers in Press, March 16, 2003. DOI 10.1194/jlr.R300002-JLR200

  2003cites this paper