| 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]
Publication Abstract from PubMed
Maturity-onset diabetes of the young (MODY3), a monogenic form of type II diabetes mellitus, results most commonly from mutations in hepatocyte nuclear factor 1alpha (HNF-1alpha). Diabetes-associated mutation G20R perturbs the dimerization domain of HNF-1alpha, an intertwined four-helix bundle. In the wild-type structure G20 participates in a Schellman motif to cap an alpha-helix; its dihedral angles lie in the right side of the Ramachandran plot (alpha(L) region; phi 97 degrees). Substitutions G20R and G20A lead to dimeric molten globules of low stability, suggesting that the impaired function of the diabetes-associated transcription factor is due in large part to a main-chain perturbation rather than to specific features of the Arg side-chain. This hypothesis is supported by the enhanced stability of non-standard analogues containing D-Ala or D-Ser at position 20. The crystal structure of the D-Ala20 analogue, determined to a resolution of 1.4 A, is essentially identical to the wild-type structure in the same crystal form. The mean root-mean-square deviation between equivalent C(alpha) atoms (residues 5-28) is 0.3 A; (phi, psi) angles of D-Ala20 are the same as those of G20 in the wild-type structure. Whereas the side-chain of A20 or R20 would be expected to clash with the preceding carbonyl oxygen (thus accounting for its frustrated energy landscape), the side-chain of D-Ala20 projects into solvent without perturbation of the Schellman motif. Calorimetric studies indicate that the increased stability of the D-Ala20 analogue (DeltaDeltaG(u) 1.5 kcal/mol) is entropic in origin, consistent with a conformational bias toward native-like conformations in the unfolded state. Studies of multiple substitutions at G20 and neighboring positions highlight the essential contributions of a glycine-specific tight turn and adjoining inter-subunit side-chain hydrogen bonds to the stability and architectural specificity of the intertwined dimer. Comparison of L- and D amino acid substitutions thus provides an example of the stereospecific control of an energy landscape by a helix-capping residue.
Diabetes mellitus due to misfolding of a beta-cell transcription factor: stereospecific frustration of a Schellman motif in HNF-1alpha.,Narayana N, Phillips NB, Hua QX, Jia W, Weiss MA J Mol Biol. 2006 Sep 22;362(3):414-29. Epub 2006 Jul 27. PMID:16930618[22]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ 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
- ↑ 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
- ↑ 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
- ↑ 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
- ↑ 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
- ↑ 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
- ↑ 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
- ↑ 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
- ↑ 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
- ↑ 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
- ↑ 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
- ↑ 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
- ↑ 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
- ↑ 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
- ↑ 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
- ↑ 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
- ↑ 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
- ↑ 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
- ↑ 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
- ↑ 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
- ↑ 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
- ↑ Narayana N, Phillips NB, Hua QX, Jia W, Weiss MA. Diabetes mellitus due to misfolding of a beta-cell transcription factor: stereospecific frustration of a Schellman motif in HNF-1alpha. J Mol Biol. 2006 Sep 22;362(3):414-29. Epub 2006 Jul 27. PMID:16930618 doi:https://dx.doi.org/S0022-2836(06)00751-0
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