A mutation in the promoter of the lipoprotein lipase (LPL) gene in a patient with familial combined hyperlipidemia and low LPL activity.

C substitution at nt -39, occurred in the binding site of the transcription factor Oct-1. As a result, the transcriptional activity of the mutant promoter was < 15% of wild type, as determined by transfection studies in the human macrophage-like cell line THP-1. This decrease in promoter activity was observed in undifferentiated as well as in phorbol ester-differentiated THP-1 cells. Furthermore, the inductive effect of elevating the levels of intracellular cAMP was equally reduced. This mutation was not present among 20 FCHL patients with normal plasma LPL levels nor has it been reported among individuals with familial LPL deficiency. Thus, heterozygosity for LPL promoter mutations may be one of several factors that contribute to the etiology of FCHL. -->
Komentáře: Erratum in: Proc Natl Acad Sci U S A 1996 Jan 9;93(1):524.
References: Am J Med. 1973 Feb;54(2):148-60. (PMID: 4346680)
Lancet. 1973 May 5;1(7810):954-9. (PMID: 4121585)
J Clin Invest. 1973 Jul;52(7):1544-68. (PMID: 4718953)
Metabolism. 1976 Mar;25(3):313-20. (PMID: 1250165)
Anal Biochem. 1976 May 7;72:248-54. (PMID: 942051)
J Lipid Res. 1983 Feb;24(2):147-55. (PMID: 6403642)
Metabolism. 1983 Dec;32(12):1107-14. (PMID: 6645961)
Proc Natl Acad Sci U S A. 1984 May;81(9):2650-4. (PMID: 6425835)
Nature. 1984 Jul 5-11;310(5972):71-4. (PMID: 6330567)
Nature. 1986 Jan 9-15;319(6049):154-8. (PMID: 3079885)
Nature. 1986 Oct 16-22;323(6089):640-3. (PMID: 3095662)
Mol Cell Biol. 1987 Feb;7(2):725-37. (PMID: 3821727)
Cell. 1987 Jun 19;49(6):741-52. (PMID: 3034433)
Biochemistry. 1988 Apr 19;27(8):2651-5. (PMID: 3401441)
Genes Dev. 1988 Dec;2(12A):1513-6. (PMID: 3215510)
CMAJ. 1989 Feb 15;140(4):405-11. (PMID: 2914262)
Nucleic Acids Res. 1989 Jul 25;17(14):5864. (PMID: 2762168)
Biochemistry. 1989 May 16;28(10):4131-5. (PMID: 2765475)
Biochemistry. 1989 May 30;28(11):4563-7. (PMID: 2765502)
Genomics. 1989 Nov;5(4):874-9. (PMID: 2687159)
Biotechniques. 1988 May;6(5):454-8. (PMID: 2908509)
Nature. 1990 May 31;345(6274):444-6. (PMID: 2342576)
Nucleic Acids Res. 1990 Jul 11;18(13):3975-82. (PMID: 1695733)
J Clin Invest. 1990 Sep;86(3):735-50. (PMID: 2394828)
Genes Dev. 1991 Jan;5(1):105-19. (PMID: 1989904)
Experientia. 1991 Jan 15;47(1):22-31. (PMID: 1999239)
Science. 1991 Aug 30;253(5023):1022-6. (PMID: 1887216)
J Biol Chem. 1991 Oct 5;266(28):18958-63. (PMID: 1918010)
Gene. 1991 Nov 15;107(2):247-58. (PMID: 1748295)
Science. 1991 Dec 20;254(5039):1814-6. (PMID: 1684878)
Biochim Biophys Acta. 1992 Jan 6;1129(2):166-71. (PMID: 1730055)
Cell. 1992 Feb 21;68(4):755-67. (PMID: 1739980)
Circulation. 1992 Jun;85(6):2025-33. (PMID: 1534286)
Curr Opin Genet Dev. 1992 Apr;2(2):199-204. (PMID: 1386267)
Arteriosclerosis. 1989 May-Jun;9(3):326-34. (PMID: 2719595)
Arterioscler Thromb. 1992 Oct;12(10):1176-83. (PMID: 1390589)
Arch Biochem Biophys. 1992 Nov 1;298(2):630-9. (PMID: 1416992)
Curr Opin Cell Biol. 1993 Jun;5(3):477-87. (PMID: 8352966)
Biochim Biophys Acta. 1993 Dec 14;1216(3):375-84. (PMID: 8268219)
Mol Cell Biol. 1994 Mar;14(3):2129-39. (PMID: 8114743)
Cell. 1994 Apr 8;77(1):21-32. (PMID: 8156594)
Blood. 1994 Jun 1;83(11):3350-5. (PMID: 7514907)
Arterioscler Thromb. 1994 Jun;14(6):869-73. (PMID: 8199176)
Arterioscler Thromb. 1994 Aug;14(8):1250-7. (PMID: 8049185)
J Clin Invest. 1994 Sep;94(3):1141-6. (PMID: 8083355)
Proc Natl Acad Sci U S A. 1994 Oct 25;91(22):10526-30. (PMID: 7937987)
Arterioscler Thromb. 1994 Nov;14(11):1687-94. (PMID: 7947591)
Grant Information: HL 30086 United States HL NHLBI NIH HHS; HL 47151 United States HL NHLBI NIH HHS
Molecular Sequence: GENBANK S78266
Substance Nomenclature: 0 (DNA Primers)
0 (DNA-Binding Proteins)
0 (HCFC1 protein, human)
0 (Host Cell Factor C1)
0 (Octamer Transcription Factor-1)
0 (POU2F1 protein, human)
0 (Recombinant Proteins)
0 (Transcription Factors)
3KX376GY7L (Glutamic Acid)
9007-49-2 (DNA)
EC 3.1.1.34 (Lipoprotein Lipase)
TE7660XO1C (Glycine)
Entry Date(s): Date Created: 19950509 Date Completed: 19950616 Latest Revision: 20190501
Update Code: 20221213
PubMed Central ID: PMC41964
DOI: 10.1073/pnas.92.10.4462
PMID: 7753827
Autor: Yang WS; Department of Medicine, University of Washington, Seattle 98195, USA., Nevin DN, Peng R, Brunzell JD, Deeb SS
Jazyk: angličtina
Zdroj: Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 1995 May 09; Vol. 92 (10), pp. 4462-6.
DOI: 10.1073/pnas.92.10.4462
Abstrakt: We have identified a naturally occurring mutation in the promoter of the lipoprotein lipase (LPL) gene. One of 20 patients with familial combined hyperlipidemia (FCHL) and reduced levels of postheparin plasma LPL activity was found to be a heterozygote carrier of this mutation. The mutation, a T-->C substitution at nt -39, occurred in the binding site of the transcription factor Oct-1. As a result, the transcriptional activity of the mutant promoter was < 15% of wild type, as determined by transfection studies in the human macrophage-like cell line THP-1. This decrease in promoter activity was observed in undifferentiated as well as in phorbol ester-differentiated THP-1 cells. Furthermore, the inductive effect of elevating the levels of intracellular cAMP was equally reduced. This mutation was not present among 20 FCHL patients with normal plasma LPL levels nor has it been reported among individuals with familial LPL deficiency. Thus, heterozygosity for LPL promoter mutations may be one of several factors that contribute to the etiology of FCHL.
Databáze: MEDLINE
Externí odkaz: