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

Abstract

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. 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. apolipoprotein very low density lipoproteins low density lipoproteins microsomal triglyceride transfer protein familial hypobetalipoproteinemia high density lipoproteins Dulbecco's modified Eagle's medium endoplasmic reticulum monoclonal antibody Apolipoprotein (apo)1 B is essential for the formation of triglyceride-rich lipoproteins, namely very low density lipoproteins (VLDL) and chylomicrons (1Chan L. J. Biol. Chem. 1992; 267: 25621-25624Abstract Full Text PDF PubMed Google Scholar). In humans, the liver secretes full-length apoB-100 containing 4536 amino acids, whereas the intestine secretes apoB-48 consisting of the amino-terminal 48% of apoB-100 (2Young S.G. Circulation. 1990; 82: 1574-1594Crossref PubMed Scopus (328) Google Scholar). Both forms of apoB are encoded by the APOB gene on chromosome 2, which spans 43 kb and contains 29 exons coding for a 14-kb mRNA (3Blackhart B.D. Ludwig E.M. Pierotti V.R. Caiati L. Onasch M.A. Wallis S.C. Powell L. Pease R. Knott T.J. Chu M.-L. J. Biol. Chem. 1986; 261: 15364-15367Abstract Full Text PDF PubMed Google Scholar, 4Knott T.J. Pease R. Powell L.M. Wallis S.C. Rall Jr., S.C. Innerarity T.L. Blackhart B. Taylor W.H. Marcel Y.L. Milne R. Johnson D. Fuller M. Lusis A.J. McCarthy B.J. Mahley R.W. Levy-Wilson B. Scott J. Nature. 1986; 323: 734-738Crossref PubMed Scopus (402) Google Scholar). ApoB-48 arises from a unique editing process in which cytosine at nucleotide position 6666 is converted to uracil, thereby generating an in-frame stop codon (5Chen S.H. Habib G. Yang C.Y. Gu Z.W. Lee R. Wang S.A. Silberman S.R. Cai S.J. Deslypere J.P. Rosseneu M. Gotto Jr., A.M. Li W.H. Chan L. Science. 1987; 238: 363-366Crossref PubMed Scopus (529) Google Scholar). The rat liver produces both apoB-100 and apoB-48, and both forms can assemble VLDL (6Elovson J. Chatterton J.E. Bell G.T. Schumaker V.N. Reuben M.A. Puppione D.L. Reeve Jr., J.R. Young N.L. J. Lipid Res. 1988; 29: 1461-1473Abstract Full Text PDF PubMed Google Scholar). A pentapartite model for apoB-100 on low density lipoproteins (LDL) has been proposed, in which the apoB polypeptide can be divided into five structurally distinct domains, namely NH2-βα1-β1-α2-β2-α3-COOH (7Segrest J.P. Jones M.K. De Loof H. Dashti N. J. Lipid Res. 2001; 42: 1346-1367Abstract Full Text Full Text PDF PubMed Google Scholar). The amino acid sequence of the βα1 domain is homologous to lamprey lipovitellin and microsomal triglyceride transfer protein (MTP) (8Mann C.J. Anderson T.A. Read J. Chester S.A. Harrison G.B. Kochl S. Ritchie P.J. Bradbury P. Hussain F.S. Amey J. Vanloo B. Rosseneu M. Infante R. Hancock J.M. Levitt D.G. Banaszak L.J. Scott J. Shoulders C.C. J. Mol. Biol. 1999; 285: 391-408Crossref PubMed Scopus (170) Google Scholar, 9Segrest J.P. Jones M.K. Dashti N. J. Lipid Res. 1999; 40: 1401-1416Abstract Full Text Full Text PDF PubMed Google Scholar). The βα1 domain of human apoB has thus been modeled on the basis of the solved lipovitellin structure, in which 13 β-strands (amino acids 21–263) form a β barrel, followed by a two-layered helical bundle consisting of 17 α-helices (amino acids 294–592).In vitro experiments suggest that the βα1 domain contains multiple MTP binding sites encompassing residues 430–570 (10Hussain M.M. Bakillah A. Nayak N. Shelness G.S. J. Biol. Chem. 1998; 273: 25612-25615Abstract Full Text Full Text PDF PubMed Scopus (84) Google Scholar), 512–721 (11Bradbury P. Mann C.J. Kochl S. Anderson T.A. Chester S.A. Hancock J.M. Ritchie P.J. Amey J. Harrison G.B. Levitt D.G. Brnaszak L.J. Scott J. Shoulders C.C. J. Biol. Chem. 1999; 274: 3159-3164Abstract Full Text Full Text PDF PubMed Scopus (83) Google Scholar), and probably 2–154 (8Mann C.J. Anderson T.A. Read J. Chester S.A. Harrison G.B. Kochl S. Ritchie P.J. Bradbury P. Hussain F.S. Amey J. Vanloo B. Rosseneu M. Infante R. Hancock J.M. Levitt D.G. Banaszak L.J. Scott J. Shoulders C.C. J. Mol. Biol. 1999; 285: 391-408Crossref PubMed Scopus (170) Google Scholar). The interaction between the apoB βα1 domain and MTP appears to be ionic; chemical modification of Lys and Arg residues within LDL or recombinant apoB-18 abolished interactions between apoB and MTP (12Bakillah A. Jamil H. Hussain M.M. Biochemistry. 1998; 37: 3727-3734Crossref PubMed Scopus (23) Google Scholar). It has been postulated that interaction of MTP and the βα1 domain of apoB creates a lipid pocket that facilitates lipid recruitment during lipoprotein assembly (9Segrest J.P. Jones M.K. Dashti N. J. Lipid Res. 1999; 40: 1401-1416Abstract Full Text Full Text PDF PubMed Google Scholar). Familial hypobetalipoproteinemia (FHBL; MIM 107730), a autosomal co-dominant disorder, is associated with reduced plasma concentrations (<5th percentile for age and sex) of apoB and β-migrating lipoproteins, as LDL and VLDL Jr., Young S.G. J. Lipid Res. Full Text PDF PubMed Google Scholar). and mutations in APOB to formation of prematurely truncated apoB forms have been in FHBL with predicted from to Jr., Young S.G. J. Lipid Res. Full Text PDF PubMed Google J.P. D. B. B. The and Molecular of Scholar). is that than with APOB can FHBL J. J. G. J. 1998; PubMed Scopus Google Scholar). than are in at concentrations of the In apoB in FHBL with truncated apoB have increased G. J. 1992; PubMed Scopus Google Scholar, S. A. M. Jr., G. G. Biol. PubMed Scopus (23) Google Scholar), decreased Young S.G. D. J. G. Biol. PubMed Scopus Google Scholar, N. G. Biol. 1999; PubMed Scopus Google Scholar), or both J.M. Biol. PubMed Scopus Google Scholar). Heterozygotes for FHBL are with LDL and apoB-100 concentrations of those in have low plasma LDL and apoB-100 and from no to and to D. L. B. B. J.R. Nature. PubMed Scopus Google Scholar), on the mutation J.P. D. B. B. The and Molecular of Scholar). is an autosomal and is by MTP D. L. B. B. J.R. Nature. PubMed Scopus Google Scholar). of naturally occurring has been in of In in human FHBL with apoB G. J. Lipid Res. 37: Full Text PDF PubMed Google and in vitro of truncated forms of human apoB Blackhart B.D. Taylor Young S.G. McCarthy B.J. J. Biol. Chem. Full Text PDF PubMed Google Scholar, D.L. Knott T.J. Pease Scott J. Biochemistry. PubMed Scopus Google Scholar, Chatterton J.E. J. Schumaker V.N. J. Biol. Chem. 1992; 267: Full Text PDF PubMed Google have the of apoB as a of VLDL assembly and in to apoB are of lipid PubMed Scopus Google and amino acid that within the amino-terminal 48% of the apoB-100 Wang Wang S. A. P. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). a novel APOB gene mutation, namely R463W found in an extended Christian Lebanese FHBL in which the mutation appears to the secretion of apoB and apoB-containing lipoproteins. The was to a lipid with on a lipid J.R. J. L. J. PubMed Scopus Google Scholar). was extended from the to a of that two and were from an was into a and a containing to and respectively, by at for at The was to high density lipoprotein LDL and liver and were using on a apoB-100 and were using on a and were by high using a was using the was from by a analysis of was by followed by with the as J.E. J. Lipid Res. 1990; Full Text PDF PubMed Google Scholar). plasma were to containing and to a as 1992; PubMed Scopus Google Scholar). The was with of R. of that an of apoB in amino acids was from The coding the and at of sequence at were using were on and using were in two using the were on the and were with sequence were on of and was in both The R463W mutation was by using a of the from the and in both analysis of and was by of from The that of the human apoB was from the M.M. Blackhart B.D. Biol. PubMed Scopus Google by with and and into J. J. Biol. Chem. Full Text PDF PubMed Google Scholar). The was as to R463W substitution using the with in To apoB-17 the encoding the amino acids of apoB followed by a stop codon was into to The R463W, and were by with the in The were by in a and coding were by for are to The are in The and the and sites are to The are in The and the and sites in a McA-RH7777 and cells were from the and were as S. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). of McA-RH7777 cells with B48 or was using the as B.D. McCarthy B.J. J. Biol. Chem. 1990; Full Text PDF PubMed Google or using the Molecular to the of apoB-17 with human MTP in cells was as S. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). of recombinant apoB and MTP was by using J. J. Biol. Chem. Full Text PDF PubMed Google and a The antibody was a of Shoulders transfected cells were with for in Dulbecco's modified Eagle's medium containing and the of the were into and lipoproteins by in a density J. Biol. Chem. 1999; 274: Full Text Full Text PDF PubMed Scopus Google Scholar). The was and by as Wang Wang S. A. P. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). transfected cells were with for in and to in Both and and The medium and apoB and or were at and were to and by associated or was by The of medium and or during was as of that associated with apoB or at the of were as G. C.J. J. L. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus (84) Google using transfected The was to the recombinant human apoB with as the The endoplasmic reticulum and the were with and respectively, with as the The were using the of was as G. C.J. J. L. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus (84) Google Scholar). In two of cells were using a was to by in a A. J. Biol. Chem. Scholar, D. J. PubMed Scopus Google Scholar). were from the of the and an of was by The proteins were and with antibody antibody and antibody the basis of protein by and were and was a of M. G. of The proteins containing the and the antibody were from and of lipid using was as J. Biol. Chem. 1999; 274: Full Text Full Text PDF PubMed Scopus Google Scholar). The model of was using the A. T.L. J. Mol. Biol. PubMed Scopus Google Scholar). of human apoB M. D. J. 1986; PubMed Scopus Google were with residues of lamprey lipovitellin T.A. J. Knott J. D. Banaszak L.J. J. Mol. Biol. 1992; PubMed Scopus Google with the of the J. Mol. Biol. 1990; PubMed Scopus Google Scholar). with the from the of lamprey lipovitellin T.A. Levitt D.G. Banaszak L.J. 1998; Full Text Full Text PDF PubMed Scopus Google Scholar), was as for were between residues in the apoB sequence during the The modeling the to residues of lipovitellin of that is from the density in the The and had a plasma of with barely detectable LDL and apoB-100. The of reduced plasma concentrations of apoB-containing lipoproteins in the of FHBL in the The and apolipoprotein for the R463W are in Heterozygotes had plasma LDL and apoB concentrations of and Heterozygotes had a in LDL and apoB-100 concentrations of and respectively, as compared with had the as a to low lipid and lipoprotein concentrations of the had or compared with had in the liver and of and with a in was was with concentrations were the in the in and the in was with both plasma and apoB the between and plasma lipid and between the lipid and and in the R463W in and LDL and were compared to and compared to and compared to and compared to and compared to and compared to are compared to are compared to are compared to are and LDL and were compared to and compared to are in a liver and concentrations in the R463W and compared to and compared to are compared to are compared to are compared to are compared to are compared to are compared to are compared to are compared to are and compared to and compared to are in a The plasma lipid and apoB-100 a co-dominant in the FHBL which the of To or the FHBL was by within the plasma apoB-100 of the by followed with the full-length apoB-100 was the or form and were no truncated forms of apoB in the plasma We sequence analysis of the human and found a of cytosine at the nucleotide of codon in in the predicted a mutation the wild-type was by at of the protein showed both cytosine and at The mutation with the in the and in the extended at of APOB in of mutation in nucleotide in was found but was a nucleotide in the with for position nucleotide with the FHBL We postulated that the R463W mutation was the of FHBL by apoB To examined the effect of R463W substitution on the secretion of apoB-48 a naturally occurring apoB form that has the to form McA-RH7777 cells were transfected with wild-type B48 or the mutant form Pulse-chase experiments with the transfected cells showed that in to B48RW was poorly secreted In secretion efficiency of B48RW was decreased by compared with that of The secreted from cells in was associated with with the density of VLDL and of B48RW associated with VLDL and was decreased compared with that of Thus, the of B48RW was secreted as whereas a was associated with VLDL and The of secreted B48RW lipoproteins, was as compared with that of of rat apoB-100 as VLDL from cells was decreased in to cells a effect of B48RW on apoB The effect of B48RW on rat secretion was in experiments and In experiments, a antibody was for that both human and rat the of the the secretion efficiency of rat was decreased by from cells as compared with that from cells The secretion of and from cells was to low of lipid Lipid analysis showed of triglyceride within the and decreased triglyceride secretion into the medium in cells as compared with those in cells of and B48 in medium lipoproteins. transfected cells were with for in containing and the were into and lipoproteins by and in were using a antibody that both recombinant human B48 and the rat apoB-100. The apoB proteins were by and by of associated with that were secreted from or the of secreted as VLDL and analysis of apoB-48 transfected cells or B48RW were with for and for to Both and and The rat and the recombinant human were from and medium by The apoB proteins were by on and by associated with and was by are expressed as of the protein at the of cells were with for in containing and the of were from cells and respectively, and by associated with and was by is the of with the The experiments that the reduced B48RW secretion was by To the to the retained showed that the of B48RW was than that of expressed in multiple transfected cells in are in with the of of B48RW in transfected cells from apoB with that from or showed of the of apoB with the To that B48RW was within the as by experiments in which the and were by using a density of proteins for and is in The of B48RW in the was than that of whereas the in the was between B48RW and suggest that the mutant B48RW have a reduced from the of of of by was as and of the were with protein containing the and and of associated with in is at the We examined the effect of R463W mutation on the secretion of apoB-17 a truncated form of apoB that poorly with but has the to with H. A. C.J. D.L. M. J. Lipid Res. 2001; 42: Full Text Full Text PDF PubMed Google and MTP M.M. Bakillah A. Jamil H. Biochemistry. PubMed Scopus Google Scholar). In transfected McA-RH7777 secretion efficiency of as by experiments, was decreased by 40% as compared with that of experiments that as was for the mutant B17RW within the with Thus, the R463W mutation in apoB-17 in reduced secretion and of and The experiments were the same as in the to that the cells were transfected with or B17RW that the R463W mutation secretion of apoB-17 as a model to the by which one amino acid substitution has a effect on apoB We Arg463 with Lys (B17RK) or Ala (B17RA) to the charge or the of the at was for apoB from a typical using cells transfected with or are in and of medium and apoB is in The secretion efficiency of was as compared with that of but the secretion of was decreased to a to that of B17RW. Thus, the positive charge at than the of the is for secretion of showed that apoB-17 to vitro M.M. Bakillah A. Jamil H. Biochemistry. PubMed Scopus Google Scholar), and the interaction to be by Lys and Arg residues within apoB (12Bakillah A. Jamil H. Hussain M.M. Biochemistry. 1998; 37: 3727-3734Crossref PubMed Scopus (23) Google Scholar). To or the R463W mutation apoB-17 and MTP into cells and their interaction within the cells by experiments The was for of apoB or MTP In transfected both and B17RW were expressed The and B17RW were both decreased by co-transfection of probably the MTP apoB-17 was the in McA-RH7777 B17RW was poorly secreted compared with from transfected of as S. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar), had no effect on or B17RW secretion The interaction between apoB-17 and MTP was by with antibody and apoB with an antibody on a The of the B17RW on the was that that of The of MTP was between and cells suggest that the R463W mutation but interaction in the transfected apoB sequence to lamprey A model of apoB-17 on the of lipovitellin predicted that Arg463 was in an extended in close proximity to residues Glu756 and Asp456 To Glu756 or Asp456 be for apoB secretion, Glu756 to Gln (B17EQ) and Asp456 to Asn (B17DN) and their secretion efficiency in transfected McA-RH7777 analysis showed that of in the B17RW and was lower than that of In of was with that of and of mutation at Glu756 and Asp456 on of the mutant that a amino acid (B17EQ) or secretion of from transfected McA-RH7777 The cells were transfected with apoB-17 as the cells were and were and an of was for using The was by proteins were a and the human proteins were with the We have discovered a novel and gene mutation, R463W, in a Christian Lebanese FHBL kindred. The mutation showed co-dominant with the FHBL and homozygotes respectively, lower than the and barely plasma apoB To date, the only that has been associated with naturally occurring mutations inAPOB is a co-dominant form of which from the LDL forms of apoB-100 the and J.P. D. B. B. The and Molecular of Scholar). The by two of mutations within the coding of the APOB gene the that apoB-100 in at both VLDL assembly and and The R463W mutation found in the FHBL a local domain that appears to be for the secretion of apoB and for lipid recruitment during lipoprotein The amino acid is within the βα1 which contains sequence that are to be for of for the interaction between MTP and and for lipoprotein have that apoB containing the βα1 domain were to be secreted D.G. Wang L. A. J.R. P. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google or secreted poorly Wang Wang S. A. P. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). have within the βα1 domain that are essential for secretion of apoB and for apoB-containing lipoprotein assembly Shelness G.S. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, J. J. Wang J. Biol. Chem. 1998; 273: Full Text Full Text PDF PubMed Scopus Google Scholar, W.H. H. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). In the two truncated forms of apoB and the R463W mutation in decreased secretion efficiency compared with of the apoB polypeptide or to assemble lipoproteins and In the of apoB-48, the R463W mutation to assemble VLDL and the A and of during VLDL assembly at a the are converted to VLDL as the P. J. S. S. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). The secretion of both VLDL and the that the R463W mutation effect at the of lipoprotein The thus for the of the βα1 The by which the R463W mutation apoB secretion has been using apoB-17 as a The proximity of R463W to the MTP binding within apoB have the FHBL in the kindred. experiments with amino acid the of the positive charge associated with experiments suggest binding of mutant apoB to in transfected the mutant apoB increased binding to MTP The binding to MTP the of the mutant proteins as by and and experiments the of the is that in transfected of B48RW in in the secretion of rat apoB-100 It is to that the effect of B48RW on rat apoB secretion is to the MTP binding of the mutant The by which of the apoB secretion to be using apoB-48 and apoB-100 as Molecular modeling of apoB-17 on the of lamprey lipovitellin that Arg463 is in an extended and is in close proximity to residues Glu756 and Asp456. substitution of Asp456 with Asn decreased suggest that the containing Asp456 and Arg463 are in apoB and MTP The the apoB encompassing Arg463 and Asp456 and MTP interaction to be in the of apoB-48 and apoB-100. The low plasma triglyceride concentrations that are typical of FHBL be at in to assembly and secretion of triglyceride-rich lipoproteins. of the of the mutant apoB was with the secretion of apoB-containing lipoproteins both in vitro J. Lipid Res. Full Text PDF PubMed Google and in Jr., Young S.G. J. Lipid Res. Full Text PDF PubMed Google Scholar). in secretion efficiency for truncated apoB forms from to In of the truncated recombinant were secreted as as apoB-100 or apoB-48 Blackhart B.D. Taylor Young S.G. McCarthy B.J. J. Biol. Chem. Full Text PDF PubMed Google Scholar, J. J. Biol. Chem. Full Text PDF PubMed Google Scholar). Thus, is that the R463W mutation, which has a than of apoB Jr., Young S.G. J. Lipid Res. Full Text PDF PubMed Google Scholar, J.P. D. B. B. The and Molecular of Scholar), can FHBL. In to secretion, increased of prematurely truncated apoB has been in FHBL G. J. 1992; PubMed Scopus Google Scholar, S. A. M. Jr., G. G. Biol. PubMed Scopus (23) Google Scholar, Young S.G. D. J. G. Biol. PubMed Scopus Google Scholar, N. G. Biol. 1999; PubMed Scopus Google Scholar, J.M. Biol. PubMed Scopus Google Scholar). a for apoB R463W the of the secreted be to be and the assembly and secretion by the to be by in lipoprotein using the human FHBL and in that the R463W mutation in APOB Lipid analysis showed that of B48RW was associated with triglyceride and decreased triglyceride secretion is that the can be in with in H. M. A. N. M. J. Google Scholar, P. A. G. L. S. S. J. Full Text Full Text PDF PubMed Scopus Google Scholar, P. A. G. L. S. R. S. J. Lipid Res. 2001; 42: Full Text Full Text PDF PubMed Google Scholar). The and in the R463W a that is with of the in mutation be of the R463W for was with the between and plasma lipid and apoB concentrations 1999; PubMed Scopus Google Scholar). homozygotes had no and were only in the is that of be In the in vitro of R463W mutation be with the assembly and secretion of apoB-containing lipoproteins in The for the secretion of VLDL and binding to the of FHBL in of R463W the extended Christian Lebanese Thus, the naturally occurring R463W mutation within the postulated binding for MTP reveals a key local domain governing assembly and secretion of apoB-containing lipoproteins. The an of analysis of a with a can into the the of of mutations inAPOB J. 2001; Full Text Full Text PDF PubMed Scopus Google Scholar). the apoB domain for of to of apoB-containing lipoproteins in as familial or which are by plasma apoB concentrations and We R. M. G. and Shoulders for and