Genetic Variation in the Hepatocyte Nuclear Factor (HNF)-3α Gene Does Not Contribute to Maturity-Onset Diabetes of the Young in Japanese

Heterozygous mutations in the genes encoding transcription factors in the hepatocyte nuclear factor (HNF) cascade are associated with maturity-onset diabetes of the young (MODY), a monogenic form of diabetes mellitus. However, these genes are responsible for only ∼ 20 % of the cases of MODY in Japanese patients. Searching for a novel MODY gene in this population, we investigated a candidate for encoding the forkhead transcription factor HNF-3α, which also belongs to the HNF-transcription cascade. The human HNF-3α gene, which was assigned to the segment near microsatellites D14S75 and AFM200ZH4 on chromosome 14 by radiation hybrid mapping, spans ∼ 5 kb and consists of two exons. Ninety-five Japanese subjects with MODY/early-onset non-ketotic diabetes were screened for mutations in this gene. Direct sequencing of the exons and flanking regions identified one missense mutation (Ala-83-Thr) in exon 2 and three nucleotide alterations in the non-coding regions. However, their frequencies were not significantly different between MODY and control subjects, indicating that mutations in the HNF-3α gene are not a major cause of MODY in Japanese patients.

Key words:

Transcription Factor - Genetics - Mutation - Polymorphism - Insulin Secretion

References

• 1 De Simone V, Cortese R. Transcription factors and liver-specific genes.  Biochim Biophys Acta. 1992;  1132 119-126
• 2 Fajans S S. Maturity-onset diabetes of the young (MODY).  Diabetes Metab Rev. 1989;  5 579-606
• 3 Yamagata K, Oda N, Kaisaki P J, Menzel S, Furuta H, Vaxillaire M, Southam L, Cox R D, Lathrop G M, Boriraj V V, Chen X, Cox N J, Oda Y, Yano H, LeBeau M M, Yamada S, Nishigori H, Takeda J, Fajans S S, Hattersley A T, Iwasaki N, Hansen T, Pedersen O, Polonsky K S, Turner R C, Velho G, Chevre J -C, Froguel P, Bell G I. Mutations in the hepatocyte nuclear factor-1α gene in maturity-onset diabetes of the young (MODY3).  Nature. 1996;  384 455-458
• 4 Dukes I D, Sreenan S, Roe M W, Levisetti M, Zhou Y -P, Ostrega D, Bell G I, Pontoglio M, Yaniv M, Philipson L, Polonsky K S. Defective pancreatic β-cell glycolytic signaling in hepatocyte nuclear factor-1α-deficient mice.  J Biol Chem. 1998;  273 24 457-24 464
• 5 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-4α gene in maturity-onset diabetes of the young (MODY1).  Nature. 1996;  384 458-460
• 6 Vaisse C, Kim J, Wspinosa III R, LeBeau M M, Stoffel M. Pancreatic islet expression studies and polymorphic DNA markers in the genes encoding hepatocyte nuclear factor-3α, -3β, -3γ, -4γ, and -6.  Diabetes. 1997;  46 1364-1367
• 7 Lai E, Darnel J E. Transcriptional control in hepatocytes: A window on development.  Trends Biochem Sci. 1991;  16 427-430
• 8 Duncan S A, Navas M A, Dufort D, Rossant J, Stoffel M. Regulation of a transcription factor network required for differentiation and metabolism.  Science. 1998;  281 692-695
• 9 Kaestner K H, Katz J, Liu Y, Drucker D J, Schutz G. Inactivation of the winged helix transcription factor HNF-3α affects glucose homeostasis and islet glucagon gene expression.  Genes Dev. 1999;  13 495-504
• 10 Shih D Q, Navas M A, Kuwajima S, Duncan S A, Stoffel M. Impaired glucose homeostasis and neonatal mortality in hepatocyte nuclear factor 3α-deficient mice.  Proc Natl Acad Sci USA. 1999;  96 10 152-10 157
• 11 Byrne M M, Sturis J, Menzel S, Yamagata K, Fajans S S, Dronsfield M J, Bain S C, Hattersle A T, Velho G, Froguel P, Bell G I, Polonsky K S. Altered insulin secretory responses to glucose in diabetic and nondiabetic subjects with mutations in the diabetes mellitus susceptibility gene MODY3 on chromosome 12q.  Diabetes. 1996;  45 1503-1510
• 12 Bingle C D, Gowan S. Molecular cloning of the forkhead transcription factor HNF-3α from a human pulmonary adenocarcinoma cell line.  Biochim Biophys Acta. 1996;  1307 17-20
• 13 Yamada S, Tomura H, Nishigori H, Sho K, Mabe H, Iwatani N, Takumi T, Kito Y, Moriya N, Muroya K, Ogata T, Onigata K, Morikawa A, Inoue I, Takeda J. Identification of mutations in the hepatocyte nuclear factor-1α gene in Japanese subjects with early-onset NIDDM and functional analysis of the mutant proteins.  Diabetes. 1999;  48 645-648
• 14 Iwasaki N, Oda N, Hara M, Hinokio Y, Oda Y, Yamagata K, Kanematsu S, Ohgawara H, Oomori Y, Bell G I. Mutations in the hepatocyte nuclear factor-1α/MODY3 gene in Japanese subjects with early- and late-onset NIDDM.  Diabetes. 1997;  46 1504-1508
• 15 Nishigori H, Yamada S, Kohama T, Utsugi T, Shimizu H, Takeuchi T, Takeda J. Mutations in the hepatocyte nuclear factor-1α gene (MODY3) are not a major cause of early-onset non-insulin-dependent (type 2) diabetes mellitus in Japanese.  J Hum Genet. 1998;  43 107-110