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Logo of jcinvestThe Journal of Clinical Investigation
J Clin Invest. 1998 February 1; 101(3): 521–526.
PMCID: PMC508593

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


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.

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Selected References

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  • DeFronzo RA. Lilly lecture 1987. The triumvirate: beta-cell, muscle, liver. A collusion responsible for NIDDM. Diabetes. 1988 Jun;37(6):667–687. [PubMed]
  • Hanis CL, Boerwinkle E, Chakraborty R, Ellsworth DL, Concannon P, Stirling B, Morrison VA, Wapelhorst B, Spielman RS, Gogolin-Ewens KJ, et al. 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. [PubMed]
  • Mahtani MM, Widén E, Lehto M, Thomas J, McCarthy M, Brayer J, Bryant B, Chan G, Daly M, Forsblom C, et al. 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. [PubMed]
  • Fajans SS. Scope and heterogeneous nature of MODY. Diabetes Care. 1990 Jan;13(1):49–64. [PubMed]
  • Yamagata K, Furuta H, Oda N, Kaisaki PJ, Menzel S, Cox NJ, Fajans SS, Signorini S, Stoffel M, Bell GI. Mutations in the hepatocyte nuclear factor-4alpha gene in maturity-onset diabetes of the young (MODY1) Nature. 1996 Dec 5;384(6608):458–460. [PubMed]
  • Froguel P, Zouali H, Vionnet N, Velho G, Vaxillaire M, Sun F, Lesage S, Stoffel M, Takeda J, Passa P, et al. 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. [PubMed]
  • Yamagata K, Oda N, Kaisaki PJ, Menzel S, Furuta H, Vaxillaire M, Southam L, Cox RD, Lathrop GM, Boriraj VV, et al. Mutations in the hepatocyte nuclear factor-1alpha gene in maturity-onset diabetes of the young (MODY3) Nature. 1996 Dec 5;384(6608):455–458. [PubMed]
  • Cereghini S. Liver-enriched transcription factors and hepatocyte differentiation. FASEB J. 1996 Feb;10(2):267–282. [PubMed]
  • Matschinsky FM. Glucokinase as glucose sensor and metabolic signal generator in pancreatic beta-cells and hepatocytes. Diabetes. 1990 Jun;39(6):647–652. [PubMed]
  • Vaxillaire M, Rouard M, Yamagata K, Oda N, Kaisaki PJ, Boriraj VV, Chevre JC, Boccio V, Cox RD, Lathrop GM, et al. 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. [PubMed]
  • Frayling TM, Bulamn MP, Ellard S, Appleton M, Dronsfield MJ, Mackie AD, Baird JD, Kaisaki PJ, Yamagata K, Bell GI, et al. 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. [PubMed]
  • Zouali H, Vaxillaire M, Lesage S, Sun F, Velho G, Vionnet N, Chiu K, Passa P, Permutt A, Demenais F, et al. Linkage analysis and molecular scanning of glucokinase gene in NIDDM families. Diabetes. 1993 Sep;42(9):1238–1245. [PubMed]
  • Lesage S, Hani EH, 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. [PubMed]
  • Zouali H, Hani EH, Philippi A, Vionnet N, Beckmann JS, 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. [PubMed]
  • Ji L, Malecki M, Warram JH, Yang Y, Rich SS, Krolewski AS. New susceptibility locus for NIDDM is localized to human chromosome 20q. Diabetes. 1997 May;46(5):876–881. [PubMed]
  • Bowden DW, Sale M, Howard TD, Qadri A, Spray BJ, Rothschild CB, Akots G, Rich SS, Freedman BI. 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. [PubMed]
  • Chartier FL, Bossu JP, Laudet V, Fruchart JC, 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. [PubMed]
  • Boussif O, Lezoualc'h F, Zanta MA, Mergny MD, Scherman D, Demeneix B, Behr JP. 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. [PubMed]
  • Spegelaere P, van Hille B, Spruyt N, Faisst S, Cornelis JJ, 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. [PMC free article] [PubMed]
  • Dignam JD, Lebovitz RM, Roeder RG. 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. [PMC free article] [PubMed]
  • Sladek FM, Zhong WM, Lai E, Darnell JE., 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. [PubMed]
  • Byrne MM, Sturis J, Fajans SS, Ortiz FJ, Stoltz A, Stoffel M, Smith MJ, Bell GI, Halter JB, Polonsky KS. 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. [PubMed]
  • Montano MM, Müller V, Trobaugh A, Katzenellenbogen BS. 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. [PubMed]
  • Tate BF, Allenby G, Pérez JR, Levin AA, Grippo JF. 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. [PubMed]
  • Hadzopoulou-Cladaras M, Kistanova E, Evagelopoulou C, Zeng S, Cladaras C, Ladias JA. Functional domains of the nuclear receptor hepatocyte nuclear factor 4. J Biol Chem. 1997 Jan 3;272(1):539–550. [PubMed]
  • Horwitz KB, Jackson TA, Bain DL, Richer JK, Takimoto GS, Tung L. Nuclear receptor coactivators and corepressors. Mol Endocrinol. 1996 Oct;10(10):1167–1177. [PubMed]
  • Bulman MP, Dronsfield MJ, Frayling T, Appleton M, Bain SC, Ellard S, Hattersley AT. 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. [PubMed]
  • Furuta H, Iwasaki N, Oda N, Hinokio Y, Horikawa Y, Yamagata K, Yano N, Sugahiro J, Ogata M, Ohgawara H, et al. 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. [PubMed]
  • Møller AM, Urhammer SA, Dalgaard LT, Reneland R, Berglund L, Hansen T, Clausen JO, 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. [PubMed]
  • Kuo CJ, Conley PB, Chen L, Sladek FM, Darnell JE, Jr, Crabtree GR. A transcriptional hierarchy involved in mammalian cell-type specification. Nature. 1992 Jan 30;355(6359):457–461. [PubMed]

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