Truncation mutations in ABCA1 suppress normal upregulation of full-length ABCA1 by 9-cis-retinoic acid and 22-R-hydroxycholesterol

Mutations in ABCA1 uniformly decrease plasma HDL-cholesterol (HDL-C) and reduce cholesterol efflux, yet different mutations in ABCA1 result in different phenotypic effects in heterozygotes. For example, truncation mutations result in significantly lower HDL-C and apoliprotein A-I (apoA-I) levels in heterozygotes compared with nontruncation mutations, suggesting that truncation mutations may negatively affect the wild-type allele. To specifically test this hypothesis, we examined ABCA1 protein expression in response to 9-cis-retinoic acid (9-cis-RA) and 22-R-hydroxycholesterol (22-R-OH-Chol) in a collection of human fibroblasts representing eight different mutations and observed that truncation mutations blunted the response to oxysterol stimulation and dominantly suppressed induction of the remaining full-length allele to 5–10% of wild-type levels. mRNA levels between truncation and nontruncation mutations were comparable, suggesting that ABCA1 expression was suppressed at the protein level. Dominant negative activity of truncated ABCA1 was recapitulated in an in vitro model using transfected Cos-7 cells. Our results suggest that the severe reduction of HDL-C in patients with truncation mutations may be at least partly explained by dominant negative suppression of expression and activity of the remaining full-length ABCA1 allele.These data suggest that ABCA1 requires a physical association with itself or other molecules for normal function and has important pharmacogenetic implications for individuals with truncation mutations. Mutations in ABCA1 uniformly decrease plasma HDL-cholesterol (HDL-C) and reduce cholesterol efflux, yet different mutations in ABCA1 result in different phenotypic effects in heterozygotes. For example, truncation mutations result in significantly lower HDL-C and apoliprotein A-I (apoA-I) levels in heterozygotes compared with nontruncation mutations, suggesting that truncation mutations may negatively affect the wild-type allele. To specifically test this hypothesis, we examined ABCA1 protein expression in response to 9-cis-retinoic acid (9-cis-RA) and 22-R-hydroxycholesterol (22-R-OH-Chol) in a collection of human fibroblasts representing eight different mutations and observed that truncation mutations blunted the response to oxysterol stimulation and dominantly suppressed induction of the remaining full-length allele to 5–10% of wild-type levels. mRNA levels between truncation and nontruncation mutations were comparable, suggesting that ABCA1 expression was suppressed at the protein level. Dominant negative activity of truncated ABCA1 was recapitulated in an in vitro model using transfected Cos-7 cells. Our results suggest that the severe reduction of HDL-C in patients with truncation mutations may be at least partly explained by dominant negative suppression of expression and activity of the remaining full-length ABCA1 allele. These data suggest that ABCA1 requires a physical association with itself or other molecules for normal function and has important pharmacogenetic implications for individuals with truncation mutations. Mutations in the ABCA1 gene have been identified as the underlying cause of Tangier Disease (TD) and of a dominantly inherited form of hypoalphalipoproteinemia (FHA) associated with reduced cellular cholesterol efflux (1Brooks-Wilson A. Marcil M. Clee S.M. Zhang L. Roomp K. van Dam M. Yu L. Brewer C. Collins J.A. Molhuizen H.O.F. Loubser O. Ouellette B.F.F. Fichter K. Ashbourne Excoffon K.J.D. Sensen C.W. Scherer S. Mott S. Denis M. Martindale D. Frohlich J. Morgan K. Koop B. Pimstone S.N. Kastelein J.J.P. Genest Jr., J. Hayden M.R. Mutations in ABCA1 in Tan-gier disease and familial high-density lipoprotein deficiency.Nat. Genet. 1999; 22: 336-345Google Scholar, 2Bodzioch M. Orsó E. Klucken J. Langmann T. Böttcher A. Diederich W. Drobnik W. Barlage S. Büchler C. Porsch-Özcürümez M. Kaminski W.E. Hahmann H.W. Oette K. Rothe G. Aslanidis C. Lackner K.J. Schmitz G. The gene encoding ATP-binding cassette transporter 1 is mutated in Tangier Disease.Nat. Genet. 1999; 22: 347-351Google Scholar, 3Rust S. Rosier M. Funke H. Amoura Z. Piette J-C. Deleuze J-F. Brewer Jr., H.B. Duverger N. Denèfle P. Assmann G. Tangier Disease is caused by mutations in the gene encoding ATP-binding cassette transporter 1.Nat. Genet. 1999; 22: 352-355Google Scholar, 4Marcil M. Brooks-Wilson A. Clee S.M. Roomp K. Zhang L. Yu L. Collins J.A. van Dam M. Molhuizen H.O.F. Loubser O. Ouellette B.F.F. Sensen C.W. Fichter K. Mott S. Denis M. Boucher B. Pimstone S. Genest Jr., J. Kastelein J.J.P. Hayden M.R. Mutations in the ABCA1 gene in familial HDL deficiency with defective cholesterol efflux.Lancet. 1999; 354: 1341-1346Google Scholar). TD is a rare form of HDL cholesterol (HDL-C) deficiency in which patients have mutations in both alleles of ABCA1, resulting in greatly impaired cholesterol efflux and virtually no circulating HDL-C (5Fredrickson D.S. Altrocchi P.H. Avioli L.V. Goodman D.W.S. Goodman H.C. Tangier Disease.Ann. Intern. Med. 1961; 55: 1016-1031Google Scholar). Intracellular cholesterol accumulation in TD patients often results in clinical manifestations of orange tonsils, hepatosplenomegaly, and peripheral neuropathy (5Fredrickson D.S. Altrocchi P.H. Avioli L.V. Goodman D.W.S. Goodman H.C. Tangier Disease.Ann. Intern. Med. 1961; 55: 1016-1031Google Scholar). Persons heterozygous for ABCA1 mutations have FHA, a less-severe clinical outcome of deficient cholesterol efflux (6Clee S.M. Kastelein J.J.P. van Dam M. Marcil M. Roomp K. Zwarts K.Y. Collins J.A. Roelants R. Tamasawa N. Stulc T. Suda T. Ceska R. Boucher B. Rondeau C. DeSouich C. Brooks-Wilson A. Molhuizen H.O.F. Frohlich J. Genest Jr., J. Hayden M.R. HDL cholesterol levels and coronary artery disease in heterozygotes for ABCA1 mutations are predicted by cholesterol efflux levels and influenced by age.J. Clin. Invest. 2000; 106: 1263-1270Google Scholar). Generally, cells of FHA patients do not have excessive intracellular cholesterol ester accumulation, a feature attributed to the activity of the remaining wild-type allele. Compared with unaffected family members, heterozygotes have HDL-C and apolipoprotein A-I (apoA-I) levels that are reduced by approximately 40% accompanied by a mild decrease in apoA-II and decreased HDL-C particle size (6Clee S.M. Kastelein J.J.P. van Dam M. Marcil M. Roomp K. Zwarts K.Y. Collins J.A. Roelants R. Tamasawa N. Stulc T. Suda T. Ceska R. Boucher B. Rondeau C. DeSouich C. Brooks-Wilson A. Molhuizen H.O.F. Frohlich J. Genest Jr., J. Hayden M.R. HDL cholesterol levels and coronary artery disease in heterozygotes for ABCA1 mutations are predicted by cholesterol efflux levels and influenced by age.J. Clin. Invest. 2000; 106: 1263-1270Google Scholar, 7Brousseau M.E. Eberhart G.P. Dupuis J. Asztalos B.F. Goldkamp A.L. Schaefer E.J. Freeman M.W. Cellular cholesterol efflux in heterozygotes for Tangier disease is markedly reduced and correlates with high density lipoprotein cholesterol concentration and particle size.J. Lipid Res. 2000; 41: 1125-1135Google Scholar). In some instances, certain FHA families have cholesterol efflux and HDL-C measurements that are considerably less than 50% of wild-type levels, raising the possibility that the function of the wild-type gene product is negatively affected by particular mutations (6Clee S.M. Kastelein J.J.P. van Dam M. Marcil M. Roomp K. Zwarts K.Y. Collins J.A. Roelants R. Tamasawa N. Stulc T. Suda T. Ceska R. Boucher B. Rondeau C. DeSouich C. Brooks-Wilson A. Molhuizen H.O.F. Frohlich J. Genest Jr., J. Hayden M.R. HDL cholesterol levels and coronary artery disease in heterozygotes for ABCA1 mutations are predicted by cholesterol efflux levels and influenced by age.J. Clin. Invest. 2000; 106: 1263-1270Google Scholar). Understanding the molecular consequences of ABCA1 mutations protein function the between ABCA1 expression and which is a the of To this we the of eight different ABCA1 mutations expression of ABCA1 mRNA and protein in fibroblasts in individuals FHA and TD families (6Clee S.M. Kastelein J.J.P. van Dam M. Marcil M. Roomp K. Zwarts K.Y. Collins J.A. Roelants R. Tamasawa N. Stulc T. Suda T. Ceska R. Boucher B. Rondeau C. DeSouich C. Brooks-Wilson A. Molhuizen H.O.F. Frohlich J. Genest Jr., J. Hayden M.R. HDL cholesterol levels and coronary artery disease in heterozygotes for ABCA1 mutations are predicted by cholesterol efflux levels and influenced by age.J. Clin. Invest. 2000; 106: 1263-1270Google Scholar). The mutations in this are the ABCA1 gene and were specifically to different and mutations. ABCA1 expression is by 9-cis-retinoic acid (9-cis-RA) and 22-R-hydroxycholesterol which the of cholesterol J.A. J. L. K. B. of and efflux of cholesterol by 2000; Scholar, K. ABCA1 gene expression and cholesterol efflux are by Res. 2000; Scholar, P. N. of the ABCA1 by the 2000; Scholar, N. P. of cholesterol efflux, and plasma in cells 2000; Scholar, H. C. of gene and Res. 2000; Scholar). we that the normal of full-length in response to is dominantly suppressed ABCA1 allele is resulting in ABCA1 protein levels that are approximately 5–10% of observed in wild-type mRNA levels. heterozygous for ABCA1 mutations TD and FHA have been (6Clee S.M. Kastelein J.J.P. van Dam M. Marcil M. Roomp K. Zwarts K.Y. Collins J.A. Roelants R. Tamasawa N. Stulc T. Suda T. Ceska R. Boucher B. Rondeau C. DeSouich C. Brooks-Wilson A. Molhuizen H.O.F. Frohlich J. Genest Jr., J. Hayden M.R. HDL cholesterol levels and coronary artery disease in heterozygotes for ABCA1 mutations are predicted by cholesterol efflux levels and influenced by age.J. Clin. Invest. 2000; 106: 1263-1270Google Scholar). heterozygous is in this is a TD and the truncation K. K. M. C. Roomp K. M. N. Zhang Z. K. A. T. M. N. H. H. C. S. Hayden M.R. T. S. and of mutations of ATP-binding cassette in patients with high-density lipoprotein Res. Scholar). have for and by the of (6Clee S.M. Kastelein J.J.P. van Dam M. Marcil M. Roomp K. Zwarts K.Y. Collins J.A. Roelants R. Tamasawa N. Stulc T. Suda T. Ceska R. Boucher B. Rondeau C. DeSouich C. Brooks-Wilson A. Molhuizen H.O.F. Frohlich J. Genest Jr., J. Hayden M.R. HDL cholesterol levels and coronary artery disease in heterozygotes for ABCA1 mutations are predicted by cholesterol efflux levels and influenced by age.J. Clin. Invest. 2000; 106: 1263-1270Google Scholar). and human fibroblasts were in with and ABCA1 expression was by the of the with with or in and in for to Cos-7 cells were in with and to cells were at with The cells at approximately were transfected using the were transfected with wild-type or truncated human ABCA1 expression with the at the to of expression in transfected cells as K. K. M. C. Roomp K. M. N. Zhang Z. K. A. T. M. N. H. H. C. S. Hayden M.R. T. S. and of mutations of ATP-binding cassette in patients with high-density lipoprotein Res. Scholar). were by in and was by at for at The was and at concentration was by a of protein were and to to with for the of ABCA1 A. A. N. R. Zhang E. O. Hayden M.R. ABCA1 mRNA and protein different and levels of Invest. as a or to the was by was by using of and to levels. was or at least and a wild-type was in of the ABCA1 and was as (1Brooks-Wilson A. Marcil M. Clee S.M. Zhang L. Roomp K. van Dam M. Yu L. Brewer C. Collins J.A. Molhuizen H.O.F. Loubser O. Ouellette B.F.F. Fichter K. Ashbourne Excoffon K.J.D. Sensen C.W. Scherer S. Mott S. Denis M. Martindale D. Frohlich J. Morgan K. Koop B. Pimstone S.N. Kastelein J.J.P. Genest Jr., J. Hayden M.R. Mutations in ABCA1 in Tan-gier disease and familial high-density lipoprotein deficiency.Nat. Genet. 1999; 22: 336-345Google Scholar). of was as (1Brooks-Wilson A. Marcil M. Clee S.M. Zhang L. Roomp K. van Dam M. Yu L. Brewer C. Collins J.A. Molhuizen H.O.F. Loubser O. Ouellette B.F.F. Fichter K. Ashbourne Excoffon K.J.D. Sensen C.W. Scherer S. Mott S. Denis M. Martindale D. Frohlich J. Morgan K. Koop B. Pimstone S.N. Kastelein J.J.P. Genest Jr., J. Hayden M.R. Mutations in ABCA1 in Tan-gier disease and familial high-density lipoprotein deficiency.Nat. Genet. 1999; 22: 336-345Google using with or and with a encoding the human ABCA1 or to the of ABCA1 to was by in 1 acid by for The was with an of with with and with 1 were in 1 for and with were in and by of were in and to were and in a 50% and ABCA1 was using a of of the ABCA1 was with using and with the at were in at and at to of ABCA1 and and the were using were an in a of of human ABCA1 and in to the and were in the as an were at for and at for were for at for and at for 1 and were to the were to the of the was in in at least For of transfected Cos-7 using or ABCA1 and were as A. A. N. R. Zhang E. O. Hayden M.R. ABCA1 mRNA and protein different and levels of Invest. Scholar). Lipid levels in TD and FHA patients were as and HDL-C was as (1Brooks-Wilson A. Marcil M. Clee S.M. Zhang L. Roomp K. van Dam M. Yu L. Brewer C. Collins J.A. Molhuizen H.O.F. Loubser O. Ouellette B.F.F. Fichter K. Ashbourne Excoffon K.J.D. Sensen C.W. Scherer S. Mott S. Denis M. Martindale D. Frohlich J. Morgan K. Koop B. Pimstone S.N. Kastelein J.J.P. Genest Jr., J. Hayden M.R. Mutations in ABCA1 in Tan-gier disease and familial high-density lipoprotein deficiency.Nat. Genet. 1999; 22: 336-345Google Scholar, 4Marcil M. Brooks-Wilson A. Clee S.M. Roomp K. Zhang L. Yu L. Collins J.A. van Dam M. Molhuizen H.O.F. Loubser O. Ouellette B.F.F. Sensen C.W. Fichter K. Mott S. Denis M. Boucher B. Pimstone S. Genest Jr., J. Kastelein J.J.P. Hayden M.R. Mutations in the ABCA1 gene in familial HDL deficiency with defective cholesterol efflux.Lancet. 1999; 354: 1341-1346Google Scholar). Cellular cholesterol efflux human fibroblasts were as (1Brooks-Wilson A. Marcil M. Clee S.M. Zhang L. Roomp K. van Dam M. Yu L. Brewer C. Collins J.A. Molhuizen H.O.F. Loubser O. Ouellette B.F.F. Fichter K. Ashbourne Excoffon K.J.D. Sensen C.W. Scherer S. Mott S. Denis M. Martindale D. Frohlich J. Morgan K. Koop B. Pimstone S.N. Kastelein J.J.P. Genest Jr., J. Hayden M.R. Mutations in ABCA1 in Tan-gier disease and familial high-density lipoprotein deficiency.Nat. Genet. 1999; 22: 336-345Google Scholar, 4Marcil M. Brooks-Wilson A. Clee S.M. Roomp K. Zhang L. Yu L. Collins J.A. van Dam M. Molhuizen H.O.F. Loubser O. Ouellette B.F.F. Sensen C.W. Fichter K. Mott S. Denis M. Boucher B. Pimstone S. Genest Jr., J. Kastelein J.J.P. Hayden M.R. Mutations in the ABCA1 gene in familial HDL deficiency with defective cholesterol efflux.Lancet. 1999; 354: 1341-1346Google Scholar, S.M. Kastelein J.J.P. van Dam M. Marcil M. Roomp K. Zwarts K.Y. Collins J.A. Roelants R. Tamasawa N. Stulc T. Suda T. Ceska R. Boucher B. Rondeau C. DeSouich C. Brooks-Wilson A. Molhuizen H.O.F. Frohlich J. Genest Jr., J. Hayden M.R. HDL cholesterol levels and coronary artery disease in heterozygotes for ABCA1 mutations are predicted by cholesterol efflux levels and influenced by age.J. Clin. Invest. 2000; 106: 1263-1270Google Scholar). efflux in the or of or was and as the of cholesterol in the to was in and as the of efflux to the efflux fibroblasts of as the Cos-7 cells were with the for the cells were with and for with The was with and with or for in the was cells were with and and efflux was as was at least in and levels in truncation nontruncation were compared using a of the of individuals HDL-C was by of ABCA1 mRNA and protein expression were using with a were using for or examined the of heterozygous individuals FHA and TD families that different ABCA1 mutations and identified an approximately decrease in HDL-C and in heterozygotes compared with unaffected family (6Clee S.M. Kastelein J.J.P. van Dam M. Marcil M. Roomp K. Zwarts K.Y. Collins J.A. Roelants R. Tamasawa N. Stulc T. Suda T. Ceska R. Boucher B. Rondeau C. DeSouich C. Brooks-Wilson A. Molhuizen H.O.F. Frohlich J. Genest Jr., J. Hayden M.R. HDL cholesterol levels and coronary artery disease in heterozygotes for ABCA1 mutations are predicted by cholesterol efflux levels and influenced by age.J. Clin. Invest. 2000; 106: 1263-1270Google Scholar). In the we individuals to be heterozygous and no the ABCA1 has yet been heterozygous K. K. M. C. Roomp K. M. N. Zhang Z. K. A. T. M. N. H. H. C. S. Hayden M.R. T. S. and of mutations of ATP-binding cassette in patients with high-density lipoprotein Res. Scholar). The in this of heterozygous To the of HDL-C and levels, heterozygous individuals families were of individuals with predicted to result in truncation of ABCA1, and mutations. The other of individuals with or that result in of a full-length allele and of the of a (6Clee S.M. Kastelein J.J.P. van Dam M. Marcil M. Roomp K. Zwarts K.Y. Collins J.A. Roelants R. Tamasawa N. Stulc T. Suda T. Ceska R. Boucher B. Rondeau C. DeSouich C. Brooks-Wilson A. Molhuizen H.O.F. Frohlich J. Genest Jr., J. Hayden M.R. HDL cholesterol levels and coronary artery disease in heterozygotes for ABCA1 mutations are predicted by cholesterol efflux levels and influenced by age.J. Clin. Invest. 2000; 106: 1263-1270Google by the the of predicted protein than that of truncation as as of the between the truncation and nontruncation no in or In and HDL-C levels were significantly reduced in heterozygotes for truncation mutations compared with nontruncation mutations and of the of HDL-C levels between the that HDL-C levels are lower levels in truncation compared with nontruncation heterozygotes not a for a truncation an HDL-C than levels were observed in approximately of nontruncation heterozygotes significantly truncation heterozygotes HDL-C levels the for and than nontruncation heterozygotes These results the that the of in ABCA1 has a HDL-C levels in and that truncation mutations HDL-C levels significantly than nontruncation mutations. to the underlying the of HDL-C levels using a collection of human fibroblasts representing eight different mutations in not ABCA1 expression in fibroblasts G. J. The of ATP-binding cassette 1 mRNA levels with cholesterol efflux 2000; we by the of ABCA1 expression in human fibroblasts and with J.A. J. L. K. B. of and efflux of cholesterol by 2000; Scholar). In human ABCA1 mRNA expression stimulation with and to levels by ABCA1 protein levels between and at and are lower at than at in fibroblasts In ABCA1 mRNA protein levels were by and both mRNA and protein levels to levels by for ABCA1 protein in the of ABCA1 mutations was by of protein human fibroblasts eight FHA and TD families that were specifically to a of ABCA1 mutations the ABCA1 The fibroblasts examined of of or and mutations of the mutations, a and mutations, be predicted to result in of of the mutated ABCA1 resulting in the of a truncated ABCA1 both in this the of ABCA1, of the human fibroblasts truncation mutations the response of the remaining full-length allele to In the of heterozygous FHA the remaining allele is wild-type and is predicted to be the TD are heterozygotes and truncation and nontruncation data by are and are as are at least as to fibroblasts the of is the heterozygous of the is the heterozygous of the is the heterozygous of the is the heterozygous of the are and are as are at least as to fibroblasts the in a The of ABCA1 protein expression in response to a with In the of ABCA1 protein in fibroblasts with or was approximately that observed in wild-type fibroblasts of stimulation was observed in FHA or TD fibroblasts that truncated allele. In the of the remaining full-length ABCA1 allele in response to was markedly reduced of ABCA1 protein levels that in of truncated the remaining full-length allele was approximately to by compared with the induction observed data different wild-type fibroblasts dominant suppression was observed in with a truncation of the allele was FHA or an TD suppression of protein expression was observed of protein was at or stimulation not These suggest that truncation mutations to or expression of full-length ABCA1 protein by a dominant negative the TD fibroblasts mutations, we the decrease in protein in heterozygous cells was to the than the truncation ABCA1 protein levels in heterozygous fibroblasts the and that the mutations were to a wild-type and were than in the or heterozygous cells that the in a decrease of no than in induction of ABCA1 protein stimulation with the of a truncation decreased ABCA1 protein by approximately compared with wild-type efflux fibroblasts that the cholesterol efflux compared with wild-type the of a a truncation decreased efflux activity to levels These data that truncation than mutations in ABCA1 dominantly expression and activity of a negative we which are for a of that result in truncation of both ABCA1 gene in cells is by of the ABCA1 a that the ABCA1 gene at the and in both and wild-type not in ABCA1 protein is by which the of to ABCA1 to other The to of wild-type ABCA1 protein by in fibroblasts truncated allele at the mRNA or protein levels. To between was fibroblasts and an with and for ABCA1 expression using using the The was with the of mRNA expression as by of wild-type that ABCA1 mRNA was in stimulation are in the of ABCA1 mRNA fibroblasts different were no between the truncation compared with nontruncation that ABCA1 mRNA is in response to in we the of induction of ABCA1 protein to the induction of ABCA1 mRNA wild-type cells and the nontruncation mutations were to levels of ABCA1 protein mRNA of the fibroblasts truncation mutations were impaired in to ABCA1 protein the induction of ABCA1 mRNA is not significantly different between truncation and nontruncation fibroblasts the to ABCA1 protein in cells truncation mutations is to decreased of the full-length allele or of the full-length protein in the of the truncated protein the that truncation mutations in ABCA1 allele dominantly protein induction of the remaining full-length allele. To test this we the of truncation mutations ABCA1 expression and cholesterol efflux activity using Cos-7 cells with wild-type and truncated or human ABCA1 transfected with wild-type ABCA1 ABCA1 protein and cholesterol efflux compared with transfected cells of wild-type and wild-type ABCA1 in a of efflux activity and that wild-type ABCA1 protein was both be that the and have different be to the levels of ABCA1 cells were with wild-type and expression of the truncated is suggesting that truncation of ABCA1 may the protein of the wild-type was reduced with truncated of ABCA1 truncated at acid significantly efflux compared with cells transfected with a of wild-type ABCA1 cells were with wild-type and ABCA1 that both alleles protein and that the of ABCA1 a not decrease the of wild-type ABCA1 efflux was to cells transfected with wild-type ABCA1 These data that truncated ABCA1 with the expression and activity of wild-type To the possibility that in mRNA expression between the and were for the observed in protein and efflux was transfected cells. The results that of the is in transfected cells that the dominant negative of ABCA1 protein levels and efflux activity at a level. The clinical of TD and FHA patients results defective efflux of cholesterol which in is a function of ABCA1 and ABCA1 protein levels in has been to HDL-C levels in in of Clee S.M. Zhang B. Brooks-Wilson A. A. N. G. C. B. Hayden M.R. ABCA1 HDL-C and efflux by an in Scholar, G. M. C. T. J. Brewer Jr., H.B. S. ABCA1 to and cholesterol in Clin. Invest. Scholar, J-F. and activity of the human ABCA1 gene in Scholar). the size of fibroblasts is is to the of ABCA1 protein and HDL-C levels in we that protein induction and HDL-C suggesting that the of ABCA1 protein expression in fibroblasts predicted HDL-C levels in ABCA1 protein levels and cholesterol efflux activity in fibroblasts was and for both of the fibroblasts ABCA1 with truncation mutations the of the of the fibroblasts nontruncation ABCA1 mutations at an between wild-type and truncation cells. ABCA1 has been identified as a of cholesterol and an important in to R. C. G. N. Clee S.M. N. J-C. Hayden M.R. ABCA1 activity Clin. Invest. Scholar). a of affected and unaffected family that to partly for other and we that ABCA1 heterozygotes have reduced HDL-C and levels that are and a for ABCA1 in HDL-C levels (6Clee S.M. Kastelein J.J.P. van Dam M. Marcil M. Roomp K. Zwarts K.Y. Collins J.A. Roelants R. Tamasawa N. Stulc T. Suda T. Ceska R. Boucher B. Rondeau C. DeSouich C. Brooks-Wilson A. Molhuizen H.O.F. Frohlich J. Genest Jr., J. Hayden M.R. HDL cholesterol levels and coronary artery disease in heterozygotes for ABCA1 mutations are predicted by cholesterol efflux levels and influenced by age.J. Clin. Invest. 2000; 106: 1263-1270Google Scholar). In this the of was by the HDL-C levels in of and and no was (6Clee S.M. Kastelein J.J.P. van Dam M. Marcil M. Roomp K. Zwarts K.Y. Collins J.A. Roelants R. Tamasawa N. Stulc T. Suda T. Ceska R. Boucher B. Rondeau C. DeSouich C. Brooks-Wilson A. Molhuizen H.O.F. Frohlich J. Genest Jr., J. Hayden M.R. HDL cholesterol levels and coronary artery disease in heterozygotes for ABCA1 mutations are predicted by cholesterol efflux levels and influenced by age.J. Clin. Invest. 2000; 106: 1263-1270Google Scholar). by the of the protein heterozygotes for truncation mutations were to have significantly lower HDL-C and levels than heterozygotes for nontruncation mutations, suggesting that truncation mutations have a in a molecular that may to the clinical of in FHA and TD the of ABCA1 expression in human fibroblasts of a of the ABCA1 protein observed a of the of ABCA1 protein to be in response to oxysterol of ABCA1 were to dominantly expression of the remaining full-length of the full-length allele was or a nontruncation In mutations that ABCA1 to in protein levels that were approximately of observed in wild-type cells. suppression of ABCA1 expression by truncation mutations at the protein ABCA1 mRNA levels are in a reduction in the of ABCA1 protein be to decreased or to of ABCA1 These may FHA or TD heterozygotes for truncation mutations are not is allele by of a severe in expression of the remaining wild-type allele is results suggest that ABCA1 protein levels HDL-C and cholesterol we observed that truncation and nontruncation mutations in between ABCA1 protein levels and HDL-C or cholesterol For both of the truncation mutations the of with dominant negative suppression of ABCA1 expression and activity by truncation mutations. These results that truncation mutations are the severe with to effects HDL-C levels, cholesterol efflux, and ABCA1 protein levels. In of the nontruncation mutations in an of the suggesting that nontruncation mutations do not have a dominant negative expression of function of the remaining ABCA1 allele. The dominant negative of ABCA1 truncation mutations was in a in vitro using Cos-7 cells transfected with expression encoding wild-type or truncated of wild-type ABCA1 with ABCA1 a not expression or efflux activity of wild-type of wild-type with truncated ABCA1 decreased cholesterol efflux wild-type ABCA1 by approximately that ABCA1 dominantly with ABCA1 Dominant negative effects are in of function and in dominant negative mutations activity the to K. B. R. of in the of that are for 2000; Scholar, S. M. of the in is by Scholar, S.M. P. of a 2000; Scholar). dominant negative mutations truncated molecules that or other L. by and in 2000; Scholar, W. C. P. B. C.W. C. B. L. Dominant negative of the is associated with a human 2000; Scholar, R. B. of gene expression by the Res. 1999; Scholar, S. H. G. mutations in the of result in Scholar). Dominant negative mutations by the function of the wild-type which often by the mutated allele a molecular or for For example, gene mutations that the function of and result in M. The molecular of and Med. Genet. 2000; Scholar). a truncation in results in a protein that with wild-type protein and dominantly to the A. C. D. of and truncation protein and disease Genet. 2000; Scholar). truncated as dominant negative of wild-type function by function and of full-length J. as negative of wild-type Scholar). The that truncation mutations in ABCA1 dominantly protein expression of full-length ABCA1 that association of ABCA1 molecules with other may be for of normal ABCA1 protein levels in cells. is that ABCA1 may form that may be for accumulation or expression at the ABCA1 is a ATP-binding cassette transporter and as for transporter function in a B. A. of the human 1999; Scholar). and form for activity H.W. The family of in Scholar, M. P. J. The cassette of 2000; Scholar, Jr., of for and 2000; Scholar, L. M. R. is a in the and of and Scholar). is less is ATP-binding cassette have the to form or other Our results suggest that may be for of protein and activity at the of truncated allele is to significantly reduce protein levels and efflux to that ABCA1 levels in cells. to ABCA1 expression we that be less in patients with truncation mutations, expression of ABCA1 impaired by the of the truncation ABCA1 or protein that at levels to ABCA1 expression or that ABCA1 the of ABCA1 with protein may be as for The and of for is by the of and the and of the of of and is by a the is by a the is an of the is a of a apolipoprotein A-I apolipoprotein 9-cis-retinoic acid hypoalphalipoproteinemia 22-R-hydroxycholesterol Tangier Disease

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