8pi8

Structural highlights

Disease

HNF1A_HUMAN Defects in HNF1A are a cause of hepatic adenomas familial (HEPAF) [MIM:142330. Hepatic adenomas are rare benign liver tumors of presumable epithelial origin that develop in an otherwise normal liver. Hepatic adenomas may be single or multiple. They consist of sheets of well-differentiated hepatocytes that contain fat and glycogen and can produce bile. Bile ducts or portal areas are absent. Kupffer cells, if present, are reduced in number and are non-functional. Conditions associated with adenomas are insulin-dependent diabetes mellitus and glycogen storage diseases (types 1 and 3). Note=Bi-allelic inactivation of HNF1A, whether sporadic or associated with MODY3, may be an early step in the developmant of some hepatocellular carcinomas. Defects in HNF1A are the cause of maturity-onset diabetes of the young type 3 (MODY3) [MIM:600496; also symbolized MODY-3. MODY is a form of diabetes that is characterized by an autosomal dominant mode of inheritance, onset in childhood or early adulthood (usually before 25 years of age), a primary defect in insulin secretion and frequent insulin-independence at the beginning of the disease.^{[1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14] [15] [16]} Defects in HNF1A are the cause of susceptibility to diabetes mellitus insulin-dependent type 20 (IDDM20) [MIM:612520. IDDM20 is a multifactorial disorder of glucose homeostasis that is characterized by susceptibility to ketoacidosis in the absence of insulin therapy. Clinical fetaures are polydipsia, polyphagia and polyuria which result from hyperglycemia-induced osmotic diuresis and secondary thirst. These features can result in long-term complications that affect the eyes, kidneys, nerves, and blood vessels.^{[17] [18] [19]}

Function

HNF1A_HUMAN Transcriptional activator that regulates the tissue specific expression of multiple genes, especially in pancreatic islet cells and in liver. Required for the expression of several liver specific genes. Binds to the inverted palindrome 5'-GTTAATNATTAAC-3'.^{[20] [21]}

References

1. ↑ Chi YI, Frantz JD, Oh BC, Hansen L, Dhe-Paganon S, Shoelson SE. Diabetes mutations delineate an atypical POU domain in HNF-1alpha. Mol Cell. 2002 Nov;10(5):1129-37. PMID:12453420
2. ↑ Rose RB, Bayle JH, Endrizzi JA, Cronk JD, Crabtree GR, Alber T. Structural basis of dimerization, coactivator recognition and MODY3 mutations in HNF-1alpha. Nat Struct Biol. 2000 Sep;7(9):744-8. PMID:10966642 doi:10.1038/78966
3. ↑ Yamagata K, Oda N, Kaisaki PJ, Menzel S, Furuta H, Vaxillaire M, Southam L, Cox RD, Lathrop GM, Boriraj VV, Chen X, Cox NJ, Oda Y, Yano H, Le Beau MM, Yamada S, Nishigori H, Takeda J, Fajans SS, Hattersley AT, Iwasaki N, Hansen T, Pedersen O, Polonsky KS, Bell GI, et al.. Mutations in the hepatocyte nuclear factor-1alpha gene in maturity-onset diabetes of the young (MODY3) Nature. 1996 Dec 5;384(6608):455-8. PMID:8945470 doi:10.1038/384455a0
4. ↑ Glucksmann MA, Lehto M, Tayber O, Scotti S, Berkemeier L, Pulido JC, Wu Y, Nir WJ, Fang L, Markel P, Munnelly KD, Goranson J, Orho M, Young BM, Whitacre JL, McMenimen C, Wantman M, Tuomi T, Warram J, Forsblom CM, Carlsson M, Rosenzweig J, Kennedy G, Duyk GM, Thomas JD, et al.. Novel mutations and a mutational hotspot in the MODY3 gene. Diabetes. 1997 Jun;46(6):1081-6. PMID:9166684
5. ↑ Iwasaki N, Oda N, Ogata M, Hara M, Hinokio Y, Oda Y, Yamagata K, Kanematsu S, Ohgawara H, Omori Y, Bell GI. Mutations in the hepatocyte nuclear factor-1alpha/MODY3 gene in Japanese subjects with early- and late-onset NIDDM. Diabetes. 1997 Sep;46(9):1504-8. PMID:9287053
6. ↑ Boutin P, Chevre JC, Hani EH, Gomis R, Pardini VC, Guillausseau PJ, Vaxillaire M, Velho G, Froguel P. An automated fluorescent single-strand conformation polymorphism technique for screening mutations in the hepatocyte nuclear factor-1alpha gene (maturity-onset diabetes of the young). Diabetes. 1997 Dec;46(12):2108-9. PMID:9392505
7. ↑ Kaisaki PJ, Menzel S, Lindner T, Oda N, Rjasanowski I, Sahm J, Meincke G, Schulze J, Schmechel H, Petzold C, Ledermann HM, Sachse G, Boriraj VV, Menzel R, Kerner W, Turner RC, Yamagata K, Bell GI. Mutations in the hepatocyte nuclear factor-1alpha gene in MODY and early-onset NIDDM: evidence for a mutational hotspot in exon 4. Diabetes. 1997 Mar;46(3):528-35. PMID:9032114
8. ↑ Frayling TM, Bulamn MP, Ellard S, Appleton M, Dronsfield MJ, Mackie AD, Baird JD, Kaisaki PJ, Yamagata K, Bell GI, Bain SC, Hattersley AT. 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):720-5. PMID:9075818
9. ↑ Hansen T, Eiberg H, Rouard M, Vaxillaire M, Moller AM, Rasmussen SK, Fridberg M, Urhammer SA, Holst JJ, Almind K, Echwald SM, Hansen L, Bell GI, Pedersen O. Novel MODY3 mutations in the hepatocyte nuclear factor-1alpha gene: evidence for a hyperexcitability of pancreatic beta-cells to intravenous secretagogues in a glucose-tolerant carrier of a P447L mutation. Diabetes. 1997 Apr;46(4):726-30. PMID:9075819
10. ↑ Vaxillaire M, Rouard M, Yamagata K, Oda N, Kaisaki PJ, Boriraj VV, Chevre JC, Boccio V, Cox RD, Lathrop GM, Dussoix P, Philippe J, Timsit J, Charpentier G, Velho G, Bell GI, Froguel P. 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):583-6. PMID:9097962
11. ↑ Chevre JC, Hani EH, Boutin P, Vaxillaire M, Blanche H, Vionnet N, Pardini VC, Timsit J, Larger E, Charpentier G, Beckers D, Maes M, Bellanne-Chantelot C, Velho G, Froguel P. Mutation screening in 18 Caucasian families suggest the existence of other MODY genes. Diabetologia. 1998 Sep;41(9):1017-23. PMID:9754819
12. ↑ Elbein SC, Teng K, Yount P, Scroggin E. Linkage and molecular scanning analyses of MODY3/hepatocyte nuclear factor-1 alpha gene in typical familial type 2 diabetes: evidence for novel mutations in exons 8 and 10. J Clin Endocrinol Metab. 1998 Jun;83(6):2059-65. PMID:9626139
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-1alpha gene in Japanese subjects with early-onset NIDDM and functional analysis of the mutant proteins. Diabetes. 1999 Mar;48(3):645-8. PMID:10078571
14. ↑ Ellard S, Bulman MP, Frayling TM, Allen LI, Dronsfield MJ, Tack CJ, Hattersley AT. Allelic drop-out in exon 2 of the hepatocyte nuclear factor-1alpha gene hinders the identification of mutations in three families with maturity-onset diabetes of the young. Diabetes. 1999 Apr;48(4):921-3. PMID:10102714
15. ↑ Ng MC, Cockburn BN, Lindner TH, Yeung VT, Chow CC, So WY, Li JK, Lo YM, Lee ZS, Cockram CS, Critchley JA, Bell GI, Chan JC. Molecular genetics of diabetes mellitus in Chinese subjects: identification of mutations in glucokinase and hepatocyte nuclear factor-1alpha genes in patients with early-onset type 2 diabetes mellitus/MODY. Diabet Med. 1999 Nov;16(11):956-63. PMID:10588527
16. ↑ Miedzybrodzka Z, Hattersley AT, Ellard S, Pearson D, de Silva D, Harvey R, Haites N. Non-penetrance in a MODY 3 family with a mutation in the hepatic nuclear factor 1alpha gene: implications for predictive testing. Eur J Hum Genet. 1999 Sep;7(6):729-32. PMID:10482964 doi:10.1038/sj.ejhg.5200358
17. ↑ Yamada S, Nishigori H, Onda H, Utsugi T, Yanagawa T, Maruyama T, Onigata K, Nagashima K, Nagai R, Morikawa A, Takeuchi T, Takeda J. Identification of mutations in the hepatocyte nuclear factor (HNF)-1 alpha gene in Japanese subjects with IDDM. Diabetes. 1997 Oct;46(10):1643-7. PMID:9313763
18. ↑ Moller AM, Dalgaard LT, Pociot F, Nerup J, Hansen T, Pedersen O. Mutations in the hepatocyte nuclear factor-1alpha gene in Caucasian families originally classified as having Type I diabetes. Diabetologia. 1998 Dec;41(12):1528-31. PMID:9867222
19. ↑ Yoshiuchi I, Yamagata K, Yang Q, Iwahashi H, Okita K, Yamamoto K, Oue T, Imagawa A, Hamaguchi T, Yamasaki T, Horikawa Y, Satoh T, Nakajima H, Miyazaki J, Higashiyama S, Miyagawa J, Namba M, Hanafusa T, Matsuzawa Y. Three new mutations in the hepatocyte nuclear factor-1alpha gene in Japanese subjects with diabetes mellitus: clinical features and functional characterization. Diabetologia. 1999 May;42(5):621-6. PMID:10333057
20. ↑ Chi YI, Frantz JD, Oh BC, Hansen L, Dhe-Paganon S, Shoelson SE. Diabetes mutations delineate an atypical POU domain in HNF-1alpha. Mol Cell. 2002 Nov;10(5):1129-37. PMID:12453420
21. ↑ Rose RB, Bayle JH, Endrizzi JA, Cronk JD, Crabtree GR, Alber T. Structural basis of dimerization, coactivator recognition and MODY3 mutations in HNF-1alpha. Nat Struct Biol. 2000 Sep;7(9):744-8. PMID:10966642 doi:10.1038/78966