Skip to main content
PMC home page
The Journal of Clinical Investigation logoLink to The Journal of Clinical Investigation
. 1998 Feb 1;101(3):521–526. doi: 10.1172/JCI1403

A missense mutation in hepatocyte nuclear factor-4 alpha, resulting in a reduced transactivation activity, in human late-onset non-insulin-dependent diabetes mellitus.

E H Hani 1, L Suaud 1, P Boutin 1, J C Chèvre 1, E Durand 1, A Philippi 1, F Demenais 1, N Vionnet 1, H Furuta 1, G Velho 1, G I Bell 1, B Laine 1, P Froguel 1
PMCID: PMC508593  PMID: 9449683

Abstract

Non-insulin-dependent diabetes mellitus (NIDDM) is a heterogeneous disorder characterized by hyperglycemia resulting from defects in insulin secretion and action. Recent studies have found mutations in the hepatocyte nuclear factor-4 alpha gene (HNF-4alpha) in families with maturity-onset diabetes of the young (MODY), an autosomal dominant form of diabetes characterized by early age at onset and a defect in glucose-stimulated insulin secretion. During the course of our search for susceptibility genes contributing to the more common late-onset NIDDM forms, we observed nominal evidence for linkage between NIDDM and markers in the region of the HNF-4alpha/MODY1 locus in a subset of French families with NIDDM diagnosed before 45 yr of age. Thus, we screened these families for mutations in the HNF-4alpha gene. We found a missense mutation, resulting in a valine-to-isoleucine substitution at codon 393 in a single family. This mutation cosegregated with diabetes and impaired insulin secretion, and was not present in 119 control subjects. Expression studies showed that this conservative substitution is associated with a marked reduction of transactivation activity, a result consistent with this mutation contributing to the insulin secretory defect observed in this family.

Full Text

The Full Text of this article is available as a PDF (295.5 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Boussif O., Lezoualc'h F., Zanta M. A., Mergny M. D., Scherman D., Demeneix B., Behr J. P. A versatile vector for gene and oligonucleotide transfer into cells in culture and in vivo: polyethylenimine. Proc Natl Acad Sci U S A. 1995 Aug 1;92(16):7297–7301. doi: 10.1073/pnas.92.16.7297. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Bowden D. W., Sale M., Howard T. D., Qadri A., Spray B. J., Rothschild C. B., Akots G., Rich S. S., Freedman B. I. Linkage of genetic markers on human chromosomes 20 and 12 to NIDDM in Caucasian sib pairs with a history of diabetic nephropathy. Diabetes. 1997 May;46(5):882–886. doi: 10.2337/diab.46.5.882. [DOI] [PubMed] [Google Scholar]
  3. Bulman M. P., Dronsfield M. J., Frayling T., Appleton M., Bain S. C., Ellard S., Hattersley A. T. A missense mutation in the hepatocyte nuclear factor 4 alpha gene in a UK pedigree with maturity-onset diabetes of the young. Diabetologia. 1997 Jul;40(7):859–862. doi: 10.1007/s001250050760. [DOI] [PubMed] [Google Scholar]
  4. Byrne M. M., Sturis J., Fajans S. S., Ortiz F. J., Stoltz A., Stoffel M., Smith M. J., Bell G. I., Halter J. B., Polonsky K. S. Altered insulin secretory responses to glucose in subjects with a mutation in the MODY1 gene on chromosome 20. Diabetes. 1995 Jun;44(6):699–704. doi: 10.2337/diab.44.6.699. [DOI] [PubMed] [Google Scholar]
  5. Cereghini S. Liver-enriched transcription factors and hepatocyte differentiation. FASEB J. 1996 Feb;10(2):267–282. [PubMed] [Google Scholar]
  6. Chartier F. L., Bossu J. P., Laudet V., Fruchart J. C., Laine B. Cloning and sequencing of cDNAs encoding the human hepatocyte nuclear factor 4 indicate the presence of two isoforms in human liver. Gene. 1994 Sep 30;147(2):269–272. doi: 10.1016/0378-1119(94)90079-5. [DOI] [PubMed] [Google Scholar]
  7. DeFronzo R. A. Lilly lecture 1987. The triumvirate: beta-cell, muscle, liver. A collusion responsible for NIDDM. Diabetes. 1988 Jun;37(6):667–687. doi: 10.2337/diab.37.6.667. [DOI] [PubMed] [Google Scholar]
  8. Dignam J. D., Lebovitz R. M., Roeder R. G. Accurate transcription initiation by RNA polymerase II in a soluble extract from isolated mammalian nuclei. Nucleic Acids Res. 1983 Mar 11;11(5):1475–1489. doi: 10.1093/nar/11.5.1475. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Fajans S. S. Scope and heterogeneous nature of MODY. Diabetes Care. 1990 Jan;13(1):49–64. doi: 10.2337/diacare.13.1.49. [DOI] [PubMed] [Google Scholar]
  10. Frayling T. M., Bulamn M. P., Ellard S., Appleton M., Dronsfield M. J., Mackie A. D., Baird J. D., Kaisaki P. J., Yamagata K., Bell G. I. Mutations in the hepatocyte nuclear factor-1alpha gene are a common cause of maturity-onset diabetes of the young in the U.K. Diabetes. 1997 Apr;46(4):720–725. doi: 10.2337/diab.46.4.720. [DOI] [PubMed] [Google Scholar]
  11. Froguel P., Zouali H., Vionnet N., Velho G., Vaxillaire M., Sun F., Lesage S., Stoffel M., Takeda J., Passa P. Familial hyperglycemia due to mutations in glucokinase. Definition of a subtype of diabetes mellitus. N Engl J Med. 1993 Mar 11;328(10):697–702. doi: 10.1056/NEJM199303113281005. [DOI] [PubMed] [Google Scholar]
  12. Furuta H., Iwasaki N., Oda N., Hinokio Y., Horikawa Y., Yamagata K., Yano N., Sugahiro J., Ogata M., Ohgawara H. Organization and partial sequence of the hepatocyte nuclear factor-4 alpha/MODY1 gene and identification of a missense mutation, R127W, in a Japanese family with MODY. Diabetes. 1997 Oct;46(10):1652–1657. doi: 10.2337/diacare.46.10.1652. [DOI] [PubMed] [Google Scholar]
  13. Hadzopoulou-Cladaras M., Kistanova E., Evagelopoulou C., Zeng S., Cladaras C., Ladias J. A. Functional domains of the nuclear receptor hepatocyte nuclear factor 4. J Biol Chem. 1997 Jan 3;272(1):539–550. doi: 10.1074/jbc.272.1.539. [DOI] [PubMed] [Google Scholar]
  14. Hanis C. L., Boerwinkle E., Chakraborty R., Ellsworth D. L., Concannon P., Stirling B., Morrison V. A., Wapelhorst B., Spielman R. S., Gogolin-Ewens K. J. A genome-wide search for human non-insulin-dependent (type 2) diabetes genes reveals a major susceptibility locus on chromosome 2. Nat Genet. 1996 Jun;13(2):161–166. doi: 10.1038/ng0696-161. [DOI] [PubMed] [Google Scholar]
  15. Horwitz K. B., Jackson T. A., Bain D. L., Richer J. K., Takimoto G. S., Tung L. Nuclear receptor coactivators and corepressors. Mol Endocrinol. 1996 Oct;10(10):1167–1177. doi: 10.1210/mend.10.10.9121485. [DOI] [PubMed] [Google Scholar]
  16. Ji L., Malecki M., Warram J. H., Yang Y., Rich S. S., Krolewski A. S. New susceptibility locus for NIDDM is localized to human chromosome 20q. Diabetes. 1997 May;46(5):876–881. doi: 10.2337/diab.46.5.876. [DOI] [PubMed] [Google Scholar]
  17. Kuo C. J., Conley P. B., Chen L., Sladek F. M., Darnell J. E., Jr, Crabtree G. R. A transcriptional hierarchy involved in mammalian cell-type specification. Nature. 1992 Jan 30;355(6359):457–461. doi: 10.1038/355457a0. [DOI] [PubMed] [Google Scholar]
  18. Lesage S., Hani E. H., Philippi A., Vaxillaire M., Hager J., Passa P., Demenais F., Froguel P., Vionnet N. Linkage analyses of the MODY3 locus on chromosome 12q with late-onset NIDDM. Diabetes. 1995 Oct;44(10):1243–1247. doi: 10.2337/diab.44.10.1243. [DOI] [PubMed] [Google Scholar]
  19. Mahtani M. M., Widén E., Lehto M., Thomas J., McCarthy M., Brayer J., Bryant B., Chan G., Daly M., Forsblom C. Mapping of a gene for type 2 diabetes associated with an insulin secretion defect by a genome scan in Finnish families. Nat Genet. 1996 Sep;14(1):90–94. doi: 10.1038/ng0996-90. [DOI] [PubMed] [Google Scholar]
  20. Matschinsky F. M. Glucokinase as glucose sensor and metabolic signal generator in pancreatic beta-cells and hepatocytes. Diabetes. 1990 Jun;39(6):647–652. doi: 10.2337/diab.39.6.647. [DOI] [PubMed] [Google Scholar]
  21. Montano M. M., Müller V., Trobaugh A., Katzenellenbogen B. S. The carboxy-terminal F domain of the human estrogen receptor: role in the transcriptional activity of the receptor and the effectiveness of antiestrogens as estrogen antagonists. Mol Endocrinol. 1995 Jul;9(7):814–825. doi: 10.1210/mend.9.7.7476965. [DOI] [PubMed] [Google Scholar]
  22. Møller A. M., Urhammer S. A., Dalgaard L. T., Reneland R., Berglund L., Hansen T., Clausen J. O., Lithell H., Pedersen O. Studies of the genetic variability of the coding region of the hepatocyte nuclear factor-4alpha in Caucasians with maturity onset NIDDM. Diabetologia. 1997 Aug;40(8):980–983. doi: 10.1007/s001250050778. [DOI] [PubMed] [Google Scholar]
  23. Sladek F. M., Zhong W. M., Lai E., Darnell J. E., Jr Liver-enriched transcription factor HNF-4 is a novel member of the steroid hormone receptor superfamily. Genes Dev. 1990 Dec;4(12B):2353–2365. doi: 10.1101/gad.4.12b.2353. [DOI] [PubMed] [Google Scholar]
  24. Spegelaere P., van Hille B., Spruyt N., Faisst S., Cornelis J. J., Rommelaere J. Initiation of transcription from the minute virus of mice P4 promoter is stimulated in rat cells expressing a c-Ha-ras oncogene. J Virol. 1991 Sep;65(9):4919–4928. doi: 10.1128/jvi.65.9.4919-4928.1991. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Tate B. F., Allenby G., Pérez J. R., Levin A. A., Grippo J. F. A systematic analysis of the AF-2 domain of human retinoic acid receptor alpha reveals amino acids critical for transcriptional activation and conformational integrity. FASEB J. 1996 Nov;10(13):1524–1531. doi: 10.1096/fasebj.10.13.8940298. [DOI] [PubMed] [Google Scholar]
  26. Vaxillaire M., Rouard M., Yamagata K., Oda N., Kaisaki P. J., Boriraj V. V., Chevre J. C., Boccio V., Cox R. D., Lathrop G. M. Identification of nine novel mutations in the hepatocyte nuclear factor 1 alpha gene associated with maturity-onset diabetes of the young (MODY3). Hum Mol Genet. 1997 Apr;6(4):583–586. doi: 10.1093/hmg/6.4.583. [DOI] [PubMed] [Google Scholar]
  27. Yamagata K., Furuta H., Oda N., Kaisaki P. J., Menzel S., Cox N. J., Fajans S. S., Signorini S., Stoffel M., Bell G. I. Mutations in the hepatocyte nuclear factor-4alpha gene in maturity-onset diabetes of the young (MODY1) Nature. 1996 Dec 5;384(6608):458–460. doi: 10.1038/384458a0. [DOI] [PubMed] [Google Scholar]
  28. Yamagata K., Oda N., Kaisaki P. J., Menzel S., Furuta H., Vaxillaire M., Southam L., Cox R. D., Lathrop G. M., Boriraj V. V. Mutations in the hepatocyte nuclear factor-1alpha gene in maturity-onset diabetes of the young (MODY3) Nature. 1996 Dec 5;384(6608):455–458. doi: 10.1038/384455a0. [DOI] [PubMed] [Google Scholar]
  29. Zouali H., Hani E. H., Philippi A., Vionnet N., Beckmann J. S., Demenais F., Froguel P. A susceptibility locus for early-onset non-insulin dependent (type 2) diabetes mellitus maps to chromosome 20q, proximal to the phosphoenolpyruvate carboxykinase gene. Hum Mol Genet. 1997 Sep;6(9):1401–1408. doi: 10.1093/hmg/6.9.1401. [DOI] [PubMed] [Google Scholar]
  30. Zouali H., Vaxillaire M., Lesage S., Sun F., Velho G., Vionnet N., Chiu K., Passa P., Permutt A., Demenais F. Linkage analysis and molecular scanning of glucokinase gene in NIDDM families. Diabetes. 1993 Sep;42(9):1238–1245. doi: 10.2337/diab.42.9.1238. [DOI] [PubMed] [Google Scholar]

Articles from Journal of Clinical Investigation are provided here courtesy of American Society for Clinical Investigation

RESOURCES