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Diabetologia
Published in: Diabetologia 4/2003

01-04-2003 | Article

T130I mutation in HNF-4α gene is a loss-of-function mutation in hepatocytes and is associated with late-onset Type 2 diabetes mellitus in Japanese subjects

Authors: Q. Zhu, K. Yamagata, A. Miura, N. Shihara, Y. Horikawa, J. Takeda, J. Miyagawa, Y. Matsuzawa

Published in: Diabetologia | Issue 4/2003

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Abstract

Aims/hypothesis

Mutations in hepatocyte nuclear factor (HNF)-4α gene cause a form of maturity-onset diabetes of the young (MODY1). The T130I mutation is a rare missense mutation, which affects a conserved amino acid in a DNA binding domain. This mutation can be found in the general population, so this variant alone does not cause MODY. However, its significance in the development of late-onset Type 2 diabetes is not known.

Methods

We screened 423 unrelated Japanese patients with late-onset Type 2 diabetes and 354 unrelated non-diabetic control subjects for the T130I mutation in the HNF-4α gene. The transactivation ability of T130I-HNF-4α was assessed using reporter gene assay.

Results

The frequency of the T130I mutation was higher in Type 2 diabetic patients (p=0.015, odds ratio 4.3, 95%CI 1.24–14.98) than control subjects. The serum HDL-cholesterol concentration was lower in Type 2 diabetic patients with the T130I mutation compared with those without this mutation (p=0.006). Reporter gene analysis showed that T130I-HNF-4α transcriptional activity was not impaired compared with wild-type HNF-4α in Hela and MIN6 cells, but it was reduced in HepG2 and primary cultured mouse hepatocytes (27–78% of wild type, p<0.05).

Conclusion/interpretation

Our findings suggest that T130I-HNF-4α is a loss-of-function mutation in hepatocytes and that this mutation is associated with late-onset Type 2 diabetes in Japanese subjects. The T130I mutation in the HNF-4α gene might be involved in the development of Type 2 diabetes in the Japanese population.
Literature
1.
Sladek FM, Zhong WM, Lai E, Darnell JE Jr (1990) Liver-enriched transcription factor HNF-4 is a novel member of the steroid hormone receptor superfamily. Genes Dev 4:2353–2365PubMed
2.
Jiang G, Sladek FM (1997) The DNA binding domain of hepatocyte nuclear factor 4 mediates cooperative, specific binding to DNA and heterodimerization with the retinoid × receptor alpha. J Biol Chem 272:1218–1225PubMed
3.
Hadzopoulou-Cladaras M, Kistanova E, Evagelopoulou C, Zeng S, Cladaras C, Ladias JA (1997) Functional domains of the nuclear receptor hepatocyte nuclear factor 4. J Biol Chem272:539–550
4.
Yamagata K, Furuta H, Oda N et al. (1996) Mutations in the hepatocyte nuclear factor-4α gene in maturity-onset diabetes of the young (MODY1). Nature 384:458–460
5.
Triggs-Raine BL, Kirkpatrick RD, Kelly SL et al. (2002) HNF-1α G319S, a transactivation-deficient mutant, is associated with altered dynamics of diabetes onset in an Oji-Cree community. Proc Natl Acad Sci USA 99:4614–4619CrossRefPubMed
6.
Zouali H, Hani EH, Philippi A et al. (1997) 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 6:1401–1408
7.
Klupa T, Malecki MT, Pezzolesi M et al. (2000) Further evidence for a susceptibility locus for type 2 diabetes on chromosome 20q13.1-q13.2. Diabetes 49:2212–2216PubMed
8.
Ghosh S, Watanabe RM, Hauser ER et al. (1999) Type 2 diabetes: evidence for linkage on chromosome 20 in 716 Finnish affected sib pairs. Proc Natl Acad Sci USA 96:2198–2203CrossRefPubMed
9.
Ghosh S, Watanabe RM, Valle TT et al. (2000) The Finland-United States investigation of non-insulin-dependent diabetes mellitus genetics (FUSION) study. I. An autosomal genome scan for genes that predispose to type 2 diabetes. Am J Hum Genet67:1174–1185
10.
Mori Y, Otabe S, Dina C et al. (2002) Genome-wide search for type 2 diabetes in Japanese affected sib-pairs confirms susceptibility genes on 3q, 15q, and 20q and identifies two new candidate Loci on 7p and 11p. Diabetes 51:1247–1255PubMed
11.
Moller AM, Urhammer SA, Dalgaard LT et al. (1997) Studies of the genetic variability of the coding region of the hepatocyte nuclear factor-4α in Caucasians with maturity onset NIDDM. Diabetologia 40:980–983CrossRefPubMed
12.
Malecki MT, Antonellis A, Casey P et al. (1998) Exclusion of the hepatocyte nuclear factor 4a as a candidate gene for late-onset NIDDM linked with chromosome 20q. Diabetes 47:970–972PubMed
13.
Sakurai K, Seki N, Fujii R et al. (2000) Mutations in the hepatocyte nuclear factor-4α gene in Japanese with non-insulin-dependent diabetes: a nucleotide substitution in the polypyrimidine tract of intron 1b. Horm Metab Res 32:316–322PubMed
14.
Yang Q, Yamagata K, Yamamoto K et al. (2000) R127W-HNF-4α is a loss of function mutation but not a rare polymorphism and causes Type II diabetes in a Japanese family with MODY1. Diabetologia 43:520–524CrossRefPubMed
15.
Shimomura I, Matsuda M, Hammer RE, Bashmakov Y, Brown MS, Goldstein JL (2000) Decreased IRS-2 and increased SREBP-1c lead to mixed insulin resistance and sensitivity in livers of lipodystrophic and ob/ob mice. Mol Cells 6:77–86
16.
Yamagata K, Yang Q, Yamamoto K et al. (1998) Mutation P291fsinsC in the transcription factor hepatocyte nuclear factor-1α is dominant negative. Diabetes 47:1231–1235PubMed
17.
Yang Q, Yamagata K, Yamamoto K et al. (1999) Structure/function studies of hepatocyte nuclear factor-1α, a diabetes-associated transcription factor. Biochem Biophys Res Commun 266:196–202CrossRefPubMed
18.
Furuta H, Iwasaki N, Oda N et al. (1997) Organization and partial sequence of the hepatocyte nuclear factor-4 α/MODY1 gene and identification of a missense mutation, R127W, in a Japanese family with MODY. Diabetes 46:1652–1657PubMed
19.
Lindner T, Gragnoli C, Furuta H et al. (1997) Hepatic function in a family with a nonsense mutation (R154X) in the hepatocyte nuclear factor-4α/MODY1 gene. J Clin Invest100:1400–1405
20.
Bulman MP, Dronsfield MJ, Frayling T et al. (1997) A missense mutation in the hepatocyte nuclear factor 4 α gene in a UK pedigree with maturity-onset diabetes of the young. Diabetologia 40:859–862CrossRefPubMed
21.
Hani EH, Suaud L, Boutin P et al. (1998) A missense mutation in hepatocyte nuclear factor-4 α, resulting in a reduced transactivation activity, in human late-onset non-insulin-dependent diabetes mellitus.J Clin Invest 101:521–526PubMed
22.
Lehto M, Wipemo C, Ivarsson SA et al. (1999) High frequency of mutations in MODY and mitochondrial genes in Scandinavian patients with familial early-onset diabetes. Diabetologia 42:1131–1137PubMed
23.
Moller AM, Dalgaard LT, Ambye L et al. (1999) A novel Phe75fsdelT mutation in the hepatocyte nuclear factor-4α gene in a Danish pedigree with maturity-onset diabetes of the young. J Clin Endocrinol Metab 84:367–369PubMed
24.
Malecki MT, Yang Y, Antonellis A, Curtis S, Warram JH, Krolewski AS (1999) Identification of new mutations in the hepatocyte nuclear factor 4α gene among families with early onset Type 2 diabetes mellitus. Diabet Med 16:193–200
25.
Bulman MP, Ellard S, Hattersley AT (2000) R127W in HNF4α is a loss-of-function mutation causing maturity-onset diabetes of the young (MODY) in a UK Caucasian family. Diabetologia 43:1203CrossRefPubMed
26.
Barrio R, Bellanne-Chantelot C, Moreno JC et al. (2002) Nine novel mutations in maturity-onset diabetes of the young (MODY) candidate genes in 22 Spanish families. J Clin Endocrinol Metab 87:2532–2539PubMed
27.
Matthews DR, Hosker JP, Rudenski AS, Naylor BA, Treacher DF, Turner RC (1985) Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia 28:412–419PubMed
28.
Byrne MM, Sturis J, Fajans SS et al. (1995) Altered insulin secretory responses to glucose in subjects with a mutation in the MODY1 gene on chromosome 20. Diabetes 44:699–704PubMed
29.
Lausen J, Thomas H, Lemm I et al. (2000) Naturally occurring mutations in the human HNF4α gene impair the function of the transcription factor to a varying degree. Nucleic Acids Res 28:430–437PubMed
30.
Yamagata K, Oda N, Kaisaki PJ et al. (1996) Mutations in the hepatocyte nuclear factor-1α gene in maturity-onset diabetes of the young (MODY3). Nature 384: 455–458
31.
Zha J, Harada H, Yang E, Jockel J, Korsmeyer SJ (1996) Serine phosphorylation of death agonist BAD in response to survival factor results in binding to 14-3-3 not BCL-X(L). Cell 87:619–628PubMed
32.
Hayhurst GP, Lee YH, Lambert G, Ward JM, Gonzalez FJ (2001) Hepatocyte nuclear factor 4α (nuclear receptor 2A1) is essential for maintenance of hepatic gene expression and lipid homeostasis. Mol Cell Biol 21:1393–1403PubMed
33.
Kim JK, Fillmore JJ, Chen Y et al. (2001) Tissue-specific overexpression of lipoprotein lipase causes tissue-specific insulin resistance. Proc Natl Acad Sci USA 98:7522–7527CrossRefPubMed
34.
Lehto M, Bitzen PO, Isomaa B et al. (1999) Mutation in the HNF-4α gene affects insulin secretion and triglyceride metabolism. Diabetes 48:423–425PubMed
35.
Shih DQ, Dansky HM, Fleisher M et al. (2000) Genotype/phenotype relationships in HNF-4α/MODY1: haploinsufficiency is associated with reduced apolipoprotein (AII), apolipoprotein (CIII), lipoprotein(a), and triglyceride levels. Diabetes 49:832–837PubMed
36.
Iwasaki N, Oda N, Ogata M et al. (1997) Mutations in the hepatocyte nuclear factor-1α/MODY3 gene in Japanese subjects with early- and late-onset NIDDM. Diabetes 46:1504–1508PubMed
37.
Urhammer SA, Rasmussen SK, Kaisaki PJ et al. (1997) Genetic variation in the hepatocyte nuclear factor-1 α gene in Danish Caucasians with late-onset NIDDM. Diabetologia 40:473–475CrossRefPubMed
38.
Yamada S, Nishigori H, Onda H (1997) Mutations in the hepatocyte nuclear factor-1α gene (MODY3) are not a major cause of late-onset NIDDM in Japanese subjects. Diabetes 46:1512–1513PubMed
Metadata
Title
T130I mutation in HNF-4α gene is a loss-of-function mutation in hepatocytes and is associated with late-onset Type 2 diabetes mellitus in Japanese subjects
Authors
Q. Zhu
K. Yamagata
A. Miura
N. Shihara
Y. Horikawa
J. Takeda
J. Miyagawa
Y. Matsuzawa
Publication date
01-04-2003
Publisher
Springer-Verlag
Published in
Diabetologia / Issue 4/2003
Print ISSN: 0012-186X
Electronic ISSN: 1432-0428
DOI
https://doi.org/10.1007/s00125-003-1067-y

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