Genetic Disorders of the Pancreatic Beta Cell and Diabetes (Permanent Neonatal Diabetes and Maturity-Onset Diabetes of the Young)

  • Emma L. Edghill
  • Andrew T. Hattersley


Mutations in critical beta-cell genes can result in monogenic diabetes. This clinically heterogeneous group of disorders usually presents soon after birth as neonatal diabetes, or during childhood or early adulthood as maturity-onset diabetes of the young (MODY). Most defects arise in genes involved in pancreatic beta-cell development or the maintenance of beta-cell function. Studying the phenotype of patients with mutations and the mechanisms by which these mutations result in diabetes gives new insights into normal and pathological functioning of the beta cell. The most common genetic etiology in patients with MODY are mutations in the genes that encode the transcription factors hepatocyte nuclear factor (HNF)-1 alpha (TCF1), HNF-4 alpha (HNF4A) and HNF-1 beta (TCF2), and the glycolytic enzyme glycokinase (GCK). Mutations in each of these genes result in different clinical phenotypes and cause beta-cell dysfunction through different mechanisms. The commonest causes of neonatal diabetes are defects in betacell function, arising from mutations in genes encoding the subunits which form the KATP channel, Kir6.2 (KCNJ11) and SUR1 (ABCC8).

Defining the genetic subtypes of monogenic diabetes not only helps understanding of the beta cell, it also has considerable implications for patient care. A genetic diagnosis provides accurate information regarding inheritance, prognosis, can explain clinical features and may guide patient treatment. The best example of pharmacogenetics is that patients with KCNJ11 mutations, despite being insulin dependent, can have excellent glycemic control on high-dose sulfonylureas. Defining the genetic etiology of monogenic diabetes has therefore contributed both to science and patient care.


Beta Cell Pancreatic Beta Cell Neonatal Diabetes Neonatal Diabetes Mellitus Monogenic Diabetes 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Flanagan SE, Edghill EL, Gloyn AL, Ellard S, Hattersley AT (2006) Mutations in KCNJ11, which encodes Kir6.2, are a common cause of diabetes diagnosed in the first 6 months of life, with the phenotype determined by genotype. Diabetologia 49: 1190–1197PubMedGoogle Scholar
  2. 2.
    Iafusco D, Stazi MA, Cotichini R, Cotellessa M, Martinucci ME, Mazzella M, Cherubini V, Barbetti F, Martinetti M, Cerutti F, Prisco F (2002) Permanent diabetes mellitus in the first year of life. Diabetologia 45:798–804PubMedGoogle Scholar
  3. 3.
    Edghill EL, Dix RJ, Flanagan SE, Bingley PJ, Hattersley AT, Ellard S, Gillespie KM (2006) HLA Genotyping supports a nonautoimmune etiology in patients diagnosed with diabetes under the age of 6 months. Diabetes 55:1895–1898PubMedGoogle Scholar
  4. 4.
    Shield JPH, Gardner RJ, Wadsworth EJK, Whiteford ML, James RS, Robinson DO, Baum JD, Temple IK (1997) Aetiopathology and genetic basis of neonatal diabetes. Arch Dis Child 76:F39–F42Google Scholar
  5. 5.
    Polak M, Shield J (2004) Neonatal and very-early-onset diabetes mellitus. Semin Neonatol 9:59–65PubMedGoogle Scholar
  6. 6.
    Temple IK, Shield JP (2002) Transient neonatal diabetes, a disorder of imprinting. J Med Genet 39:872–875PubMedGoogle Scholar
  7. 7.
    Temple IK, Gardner RJ, Mackay DJ, Barber JC, Robinson DO, Shield JP (2000) Transient neonatal diabetes: widening the understanding of the etiopathogenesis of diabetes. Diabetes 49:1359–1366PubMedGoogle Scholar
  8. 8.
    Gloyn AL, Reimann F, Girard C, Edghill EL, Proks P, Pearson ER, Temple IK, Mackay DJ, Shield JP, Freedenberg D, Noyes K, Ellard S, Ashcroft FM, Gribble FM, Hattersley AT (2005) Relapsing diabetes can result from moderately activating mutations in KCNJ11. Hum Mol Genet 14:925–934PubMedGoogle Scholar
  9. 9.
    Babenko AP, Polak M, Cave H, Busiah K, Czernichow P, Scharfmann R, Bryan J, Aguilar-Bryan L, Vaxillaire M, Froguel P (2006) Activating mutations in ABCC8 cause neonatal diabetes mellitus. N Engl J Med 355:456–466PubMedGoogle Scholar
  10. 10.
    Stoffers DA, Zinkin NT, Stanojevic V, Clarke WL, Habener JF (1997) Pancreatic agenesis attributable to a single nucleotide deletion in the human IPF1 gene coding sequence. Nat Genet 15:106–110PubMedGoogle Scholar
  11. 11.
    Schwitzgebel VM, Mamin A, Brun T, Ritz-Laser B, Zaiko M, Maret A, Jornayvaz FR, Theintz GE, Michielin O, Melloul D, Philippe J (2003) Agenesis of human pancreas due to decreased half-life of insulin promoter factor 1. J Clin Endocrinol Metab 88:4398–4406PubMedGoogle Scholar
  12. 12.
    Stoffers DA, Ferrer J, Clarke WL, Habener JF (1997) Early-onset type-II diabetes mellitus (MODY4) linked to IPF1. Nat Genet 17:138–139PubMedGoogle Scholar
  13. 13.
    Johnsson JL, Carlsson T, Edlund T, Edlund H (1994) Insulin promoter factor 1 is required for pancreas development in mice. Nature 371:606–609Google Scholar
  14. 14.
    Sellick GS, Barker KT, Stolte-Dijkstra I, Fleischmann C, R JC, Garrett C, Gloyn AL, Edghill EL, Hattersley AT, Wellauer PK, Goodwin G, Houlston RS (2004) Mutations in PTF1A cause pancreatic and cerebellar agenesis. Nat Genet 36:1301–1305PubMedGoogle Scholar
  15. 15.
    Hoveyda N, Shield JP, Garrett C, Chong WK, Beardsall K, Bentsi-Enchill E, Mallya H, Thompson MH (1999) Neonatal diabetes mellitus and cerebellar hypoplasia/agenesis: report of a new recessive syndrome. J Med Genet 36:700–704PubMedGoogle Scholar
  16. 16.
    Zecchin E, Mavropoulos A, Devos N, Filippi A, Tiso N, Meyer D, Peers B, Bortolussi M, Argenton F (2004) Evolutionary conserved role of ptf1a in the specification of exocrine pancreatic fates. Dev Biol 268:174–184PubMedGoogle Scholar
  17. 17.
    Krapp A, Knofler M, Frutiger S, Hughes GJ, Hagenbuchle O, Wellauer PK (1996) The p48 DNA-binding subunit of transcription factor PTF1 is a new exocrine pancreas-specific basic helix-loop-helix protein. EMBO J 15:4317–4329PubMedGoogle Scholar
  18. 18.
    Obata J, Yano M, Mimura H, Goto T, Nakayama R, Mibu Y, Oka C, Kawaichi M (2001) p48 subunit of mouse PTF1 binds to RBP-Jkappa/CBF-1, the intracellular mediator of Notch signalling, and is expressed in the neural tube of early stage embryos. Genes Cells 6:345–360PubMedGoogle Scholar
  19. 19.
    Yorifuji T, Kurokawa K, Mamada M, Imai T, Kawai M, Nishi Y, Shishido S, Hasegawa Y, Nakahata T (2004) Neonatal diabetes mellitus and neonatal polycystic, dysplastic kidneys: Phenotypically discordant recurrence of a mutation in the hepatocyte nuclear factor-1beta gene due to germline mosaicism. J Clin Endocrinol Metab 89: 2905–2908PubMedGoogle Scholar
  20. 20.
    Edghill EL, Ellard S, Noordam C, Minton JAL, Slingerland A, Hattersley AT (2006) Hepatocyte nuclear factor-1 beta mutations cause neonatal diabetes and intra uterine growth retardation: support for a critical role of HNF-1beta in human pancreatic development. Diabet Med 23:1301–1306PubMedGoogle Scholar
  21. 21.
    Maestro MA, Boj SF, Luco RF, Pierreux CE, Cabedo J, Servitja JM, German MS, Rousseau GG, Lemaigre FP, Ferrer J (2003) Hnf6 and Tcf2 (MODY5) are linked in a gene network operating in a precursor cell domain of the embryonic pancreas. Hum Mol Genet 12:3307–3314PubMedGoogle Scholar
  22. 22.
    Haumaitre C, Barbacci E, Jenny M, Ott MO, Gradwohl G, Cereghini S (2005) Lack of TCF2/vHNF1 in mice leads to pancreas agenesis. Proc Natl Acad Sci USA 102: 1490–1495PubMedGoogle Scholar
  23. 23.
    Senee V, Chelala C, Duchatelet S, Feng D, Blanc H, Cossec JC, Charon C, Nicolino M, Boileau P, Cavener DR, Bougneres P, Taha D, Julier C (2006) Mutations in GLIS3 are responsible for a rare syndrome with neonatal diabetes mellitus and congenital hypothyroidism. Nat Genet 38:682–687PubMedGoogle Scholar
  24. 24.
    Taha D, Barbar M, Kanaan H, Williamson Balfe J (2003) Neonatal diabetes mellitus, congenital hypothyroidism, hepatic fibrosis, polycystic kidneys, and congenital glaucoma: a new autosomal recessive syndrome? Am J Med Genet A 122: 269–273PubMedGoogle Scholar
  25. 25.
    Delepine M, Nicolino M, Barrett T, Golamaully M, Lathrop GM, Julier C (2000) EIF2AK3, encoding translation initiation factor 2-alpha kinase 3, is mutated in patients with Wolcott-Rallison syndrome. Nat Genet 25:406–409PubMedGoogle Scholar
  26. 26.
    Biason-Lauber A, Lang-Muritano M, Vaccaro T, Schoenle EJ (2002) Loss of kinase activity in a patient with Wolcott-Rallison syndrome caused by a novel mutation in the EIF2AK3 gene. Diabetes 51:2301–2305PubMedGoogle Scholar
  27. 27.
    Senee V, Vattem KM, Delepine M, Rainbow LA, Haton C, Lecoq A, Shaw NJ, Robert JJ, Rooman R, Diatloff-Zito C, Michaud JL, Bin-Abbas B, Taha D, Zabel B, Franceschini P, Topaloglu AK, Lathrop GM, Barrett TG, Nicolino M, Wek RC, Julier C (2004) Wolcott-Rallison Syndrome: clinical, genetic, and functional study of EIF2AK3 mutations and suggestion of genetic heterogeneity. Diabetes 53:1876–1883PubMedGoogle Scholar
  28. 28.
    Brickwood S, Bonthron DT, Al-Gazali LI, Piper K, Hearn T, Wilson DI, Hanley NA (2003) Wolcott-Rallison syndrome: pathogenic insights into neonatal diabetes from new mutation and expression studies of EIF2AK3. J Med Genet 40:685–689PubMedGoogle Scholar
  29. 29.
    Iyer S, Korada M, Rainbow L, Kirk J, Brown RM, Shaw N, Barrett TG (2004) Wolcott-Rallison syndrome: a clinical and genetic study of three children, novel mutation in EIF2AK3 and a review of the literature. Acta Paediatr 93:1195–1201PubMedGoogle Scholar
  30. 30.
    Harding HP, Zeng H, Zhang Y, Jungries R, Chung P, Plesken H, Sabatini DD, Ron D (2001) Diabetes mellitus and exocrine pancreatic dysfunction in perk-/-mice reveals a role for translational control in secretory cell survival. Mol Cell 7:1153–1163PubMedGoogle Scholar
  31. 31.
    Shi Y, Vattem KM, Sood R, An J, Liang J, Stramm L, Wek RC (1998) Identification and characterization of pancreatic eukaryotic initiation factor 2 alpha-subunit kinase, PEK, involved in translational control. Mol Cell Biol 18:7499–7509PubMedGoogle Scholar
  32. 32.
    Bennett CL, Ochs HD (2001) IPEX is a unique X-linked syndrome characterized by immune dysfunction, polyendocrinopathy, enteropathy, and a variety of autoimmune phenomena. Curr Opin Pediatr 13:533–538PubMedGoogle Scholar
  33. 33.
    Powell BR, Buist NR, Stenzel P (1982) An X-linked syndrome of diarrhea, polyendocrinopathy, and fatal infection in infancy. J Pediatr 100:731–737PubMedGoogle Scholar
  34. 34.
    Wildin RS, Freitas A (2005) IPEX and FOXP3: clinical and research perspectives. J Autoimmun 25Suppl:56–62PubMedGoogle Scholar
  35. 35.
    Fontenot JD, Gavin MA, Rudensky AY (2003) Foxp3 programs the development and function of CD4+CD25+ regulatory T cells. Nat Immunol 4:330–336PubMedGoogle Scholar
  36. 36.
    Gloyn AL, Pearson ER, Antcliff JF, Proks P, Bruining GJ, Slingerland AS, Howard N, Srinivasan S, Silva JM, Molnes J, Edghill EL, Frayling TM, Temple IK, Mackay D, Shield JP, Sumnik Z, van Rhijn A, Wales JK, Clark P, Gorman S, Aisenberg J, Ellard S, Njolstad PR, Ashcroft FM, Hattersley AT (2004) Activating mutations in the gene encoding the ATP-sensitive potassium-channel subunit Kir6.2 and permanent neonatal diabetes. N Engl J Med 350:1838–1849PubMedGoogle Scholar
  37. 37.
    Gloyn AL, Cummings EA, Edghill EL, Harries LW, Scott R, Costa T, Temple IK, Hattersley AT, Ellard S (2004) Permanent neonatal diabetes due to paternal germline mosaicism for an activating mutation of the KCNJ11 Gene encoding the Kir6.2 subunit of the beta-cell potassium adenosine triphosphate channel. J Clin Endocrinol Metab 89:3932–3935PubMedGoogle Scholar
  38. 38.
    Slingerland AS, Hattersley AT (2006) Activating mutations in the gene encoding kir6.2 alter fetal and postnatal growth and also cause neonatal diabetes. J Clin Endocrinol Metab 91:2782–2788PubMedGoogle Scholar
  39. 39.
    Hattersley AT, Ashcroft FM (2005) Activating mutations in Kir6.2 and neonatal diabetes: new clinical syndromes, new scientific insights, and new therapy. Diabetes 54:2503–2513PubMedGoogle Scholar
  40. 40.
    Sagen JV, Raeder H, Hathout E, Shehadeh N, Gudmundsson K, Baevre H, Abuelo D, Phornphutkul C, Molnes J, Bell GI, Gloyn AL, Hattersley AT, Molven A, Sovik O, Njolstad PR (2004) Permanent neonatal diabetes due to mutations in KCNJ11 encoding Kir6.2: patient characteristics and initial response to sulfonylurea therapy. Diabetes 53:2713–2718PubMedGoogle Scholar
  41. 41.
    Zung A, Glaser B, Nimri R, Zadik Z (2004) Glibenclamide treatment in permanent neonatal diabetes mellitus due to an activating mutation in Kir6.2. J Clin Endocrinol Metab 89:5504–5507PubMedGoogle Scholar
  42. 42.
    Pearson ER, flechtner I, Njolstad PR, Maleki MT, Flanagan S.E, Larkin B, Ashcroft FM, Kilmes I, Codner E, Iotova V, Slingerland AS, Shield J, Robert J-J, Holst JJ, Clark CM, Ellard S, Sovik O, Polak M, Hattersley AT (2006) Switching from insulin to oral sulfonylureas in patients with diabetes due to kir6.2 mutations. N Engl J Med 355:467–477PubMedGoogle Scholar
  43. 43.
    Proks P, Antcliff JF, Lippiat J, Gloyn AL, Hattersley AT, Ashcroft FM (2004) Molecular basis of Kir6.2 mutations associated with neonatal diabetes or neonatal diabetes plus neurological features. Proc Natl Acad Sci USA 101:17539–17544PubMedGoogle Scholar
  44. 44.
    Koster JC, Remedi MS, Dao C, Nichols CG (2005) ATP and sulfonylurea sensitivity of mutant ATP-sensitive K+ channels in neonatal diabetes: implications for pharmacogenomic therapy. Diabetes 54:2645–2654PubMedGoogle Scholar
  45. 45.
    Antcliff JF, Haider S, Proks P, Sansom MS, Ashcroft FM (2005) Functional analysis of a structural model of the ATP-binding site of the KATP channel Kir6.2 subunit. EMBO J 24:229–239PubMedGoogle Scholar
  46. 46.
    Proks P, Arnold AL, Bruining J, Girard C, Flanagan SE, Larkin B, Colclough K, Hattersley AT, Ashcroft FM, Ellard S (2006) A heterozygous activating mutation in the sulphonylurea receptor SUR1 (ABCC8) causes neonatal diabetes. Hum Mol Genet 15:1793–1800PubMedGoogle Scholar
  47. 47.
    Njolstad PR, Sovik O, Cuesta-Munoz A, Bjorkhaug L, Massa O, Barbetti F, Undlien DE, Shiota C, Magnuson MA, Molven A, Matschinsky FM, Bell GI (2001) Neonatal diabetes mellitus due to complete glucokinase deficiency. N Engl J Med 344:1588–1592PubMedGoogle Scholar
  48. 48.
    Glaser B, Kesavan P, Haymen M, Davies E, Cuesta A, Buchs A, Stanley CA, Thornton PS, Permutt MA, Matschinsky FM, Herold KC (1998) Familial hyper insulinism caused by an activating glucokinase mutation. N Engl J Med 338:226–230PubMedGoogle Scholar
  49. 49.
    Njolstad PR, Sagen JV, Bjorkhaug L, Odili S, Shehadeh N, Bakry D, Sarici SU, Alpay F, Molnes J, Molven A, Sovik O, Matschinsky FM (2003) Permanent neonatal diabetes caused by glucokinase deficiency: inborn error of the glucose-insulin signaling pathway. Diabetes 52:2854–2860PubMedGoogle Scholar
  50. 50.
    Santer R, Schneppenheim R, Dombrowski A, Gotze H, Steinmann B, Schaub J (1997) Mutations in GLUT2, the gene for the liver-type glucose transporter, in patients with Fanconi-Bickel syndrome. Nat Genet 17:324–326PubMedGoogle Scholar
  51. 51.
    Yoo HW, Shin YL, Seo EJ, Kim GH (2002) Identification of a novel mutation in the GLUT2 gene in a patient with Fanconi-Bickel syndrome presenting with neonatal diabetes mellitus and galactosaemia. Eur J Pediatr 161:351–353PubMedGoogle Scholar
  52. 52.
    Owen K, Hattersley AT (2001) Maturity-onset diabetes of the young: from clinical description to molecular genetic characterization. Best Pract Res Clin Endocrinol Metab 15:309–323.PubMedGoogle Scholar
  53. 53.
    Fajans SS, Bell GI, Bowden DW (1992) MODY: a model for the study of the molecular genetics of NIDDM. [Review]. J Lab Clin Mede 119:206–210Google Scholar
  54. 54.
    Froguel P, Vaxillaire M, Sun F, Velho G, Zouali H, Butel MO, Lesage S, Vionnet N, Clement K, Fougerousse F, Tanizawa Y, Weissenbach J, Beckmann JS, Lathrop GM, Passa P, Permutt MA, Cohen D (1992) Close linkage of glucokinase locus on chromosome 7p to early-onset non-insulin-dependent diabetes mellitus. Nature 356:162–164PubMedGoogle Scholar
  55. 55.
    Hattersley AT, Turner RC, Permutt MA, Patel P, Tanizawa Y, Chiu KC, O’Rahilly S, Watkins PJ, Wainscoat JS (1992) Linkage of type 2 diabetes to the glucokinase gene. Lancet 339:1307–1310PubMedGoogle Scholar
  56. 56.
    Gloyn AL (2003) Glucokinase (GCK) mutations in hyper-and hypoglycemia: Maturity-onset diabetes of the young, permanent neonatal diabetes, and hyperinsulinemia of infancy. Hum Mutat 22:353–362PubMedGoogle Scholar
  57. 57.
    Hattersley AT (1996) Glucokinase mutations and Type 2 diabetes. In: Lightman S (ed) Horizons in medicine. Blackwell Science, Bristol, pp 440–449Google Scholar
  58. 58.
    Gloyn AL, Ellard S (2006) Defining the genetic aetiology of diabetes can improve treatment. Expert Opin Biol Ther 7:1759–1767Google Scholar
  59. 59.
    Stride A, Vaxillaire M, Tuomi T, Barbetti F, Njolstad PR, Hansen T, Costa A, Conget I, Pedersen O, Sovik O, Lorini R, Groop L, Froguel P, Hattersley AT (2002) The genetic abnormality in the beta cell determines the response to an oral glucose load. Diabetologia 45:427–435PubMedGoogle Scholar
  60. 60.
    Pearson ER, Velho G, Clark P, Stride A, Shepherd M, Frayling TM, Bulman MP, Ellard S, Froguel P, Hattersley AT (2001) beta-cell genes and diabetes: quantitative and qualitative differences in the pathophysiology of hepatic nuclear factor-1alpha and glucokinase mutations. Diabetes 50:S101–S107PubMedGoogle Scholar
  61. 61.
    Prisco F, Iafusco D, Franzese A, Sulli N, Barbetti F (2000) MODY 2 presenting as neonatal hyperglycaemia: a need to reshape the definition of “neonatal diabetes”? Diabetologia 43:1331–1332PubMedGoogle Scholar
  62. 62.
    Hattersley AT, Beards F, Ballantyne E, Appleton M, Harvey R, Ellard S (1998) Mutations in the glucokinase gene of the fetus in reduced birthweight. Nat Genet 19:268–270PubMedGoogle Scholar
  63. 63.
    Appleton M, Ellard S, Bulman M, Frayling T, Page R, Hattersley AT (1997) Clinical characteristics of the HNF1alpha (MODY3) and glucokinase mutations. Diabetologia 40:A161Google Scholar
  64. 64.
    Froguel P, Zouali H, Vionnet N, Velho G, Vaxillaire M, Sun F, Lesage S, Stoffel M, Takeda J, Passa P, et al (1993) Familial hyperglycemia due to mutations in glucokinase. Definition of a subtype of diabetes mellitus. N Engl J Med 328:697–702PubMedGoogle Scholar
  65. 65.
    Page RC, Hattersley AT, Levy JC, Barrow B, Patel P, Lo D, Wainscoat JS, Permutt MA, Bell GI, Turner RC (1995) Clinical characteristics of subjects with a missense mutation in glucokinase. Diab Med 12:209–217Google Scholar
  66. 66.
    Matschinsky FM (1990) Glucokinase as glucose sensor and metabolic signal generator in pancreatic beta-cells and hepatocytes. Diabetes 39:647–652PubMedGoogle Scholar
  67. 67.
    Gidh-Jain M, Takeda J, Xu LZ (1993) Glucokinase mutations associated with noninsulin dependent (type 2) diabetes mellitus have decreased enzymatic activity: implications for structure/function relationships. Proc Nat Acad Sci USA 90: 1932–1936PubMedGoogle Scholar
  68. 68.
    Burke CV, Buettger CW, Davis EA, McClane SJ, Matschinsky FM, Raper SE (1999) Cell-biological assessment of human glucokinase mutants causing maturity-onset diabetes of the young type 2 (MODY-2) or glucokinase-linked hyperinsulinaemia (GK-HI). Biochem J 342:345–352PubMedGoogle Scholar
  69. 69.
    Shih DQ, Stoffel M (2001) Dissecting the transcriptional network of pancreatic islets during development and differentiation. Proc Natl Acad Sci USA 98:14189–14191.PubMedGoogle Scholar
  70. 70.
    Rey-Campos J, Chouard T, Yaniv M, Cereghini S (1991) vHNF1 is a homeoprotein that activates transcription and forms heterodimers with HNF1. EMBO J 10: 1445–1457PubMedGoogle Scholar
  71. 71.
    Boj SF, Parrizas M, Maestro MA, Ferrer J (2001) A transcription factor regulatory circuit in differentiated pancreatic cells. Proc Natl Acad Sci USA 98:14481–14486PubMedGoogle Scholar
  72. 72.
    Ferrer J (2002) A genetic switch in pancreatic beta-cells: implications for differentiation and haploinsufficiency. Diabetes 51:2355–2362PubMedGoogle Scholar
  73. 73.
    Bell GI, Xiang KS, Newman MV (1991) Gene for non-insulin dependent diabetes mellitus (maturity-onset diabetes of the young subtype) is linked to DNA polymorphism on human chromosome 20q. Proc Nat Acad Sci USA 88:1484–1488PubMedGoogle Scholar
  74. 74.
    Yamagata K, Furuta H, Oda N, Kaisaki PJ, Menzel S, Cox NJ, Fajans SS, Signorini S, Stoffel M, Bell GI (1996) Mutations in the hepatocyte nuclear factor 4 alpha gene in maturity-onset diabetes of the young (MODY1). Nature 384:458–460PubMedGoogle Scholar
  75. 75.
    Ryffel GU (2001) Mutations in the human genes encoding the transcription factors of the hepatocyte nuclear factor (HNF)1 and HNF4 families: functional and pathological consequences. J Mol Endocrinol 27:11–29PubMedGoogle Scholar
  76. 76.
    Ellard S, Colclough K (2006) Mutations in the gene encoding the transcription factors hepatocyte nuclear factor 1 alpha (HNF1A) and 4 alpha (HNF4A) in maturity-onset diabetes of the young. Hum Mutat 7:854–869Google Scholar
  77. 77.
    Pearson ER, Pruhova S, Tack CJ, Johansen A, Castleden HA, Lumb PJ, Wierzbicki AS, Clark PM, Lebl J, Pedersen O, Ellard S, Hansen T, Hattersley AT (2005) Molecular genetics and phenotypic characteristics of MODY caused by hepatocyte nuclear factor 4alpha mutations in a large European collection. Diabetologia 48:878–885PubMedGoogle Scholar
  78. 78.
    Byrne MM, Sturis J, Fajans SS, Ortiz FJ, Stoltz A, Stoffel M, Smith MJ, Bell GI, Halter JB, Polonsky KS (1995) Altered insulin secretory responses to glucose in subjects with a mutation in the MODY1 gene on chromosome 20. Diabetes 44:699–704PubMedGoogle Scholar
  79. 79.
    Fajans SS, Brown MB (1993) Administration of sulfonylureas can increase glucoseinduced insulin secretion for decades in patients with maturity-onset diabetes of the young. Diabetes Care 16:1254–1261PubMedGoogle Scholar
  80. 80.
    Steele AM, Barrett TG, Stals K, Shields JPH, Tysoe C, Ellard, Hattersley AT, Pearson ER (2006) A novel cause of hyperinsulinaemic hypoglycaemia with increased birthweight due to heterozygous mutations in the HNF4A gene. Diabet Med 23:3Google Scholar
  81. 81.
    Lehto M, Bitzen PO, Isomaa B, Wipemo C, Wessman Y, Forsblom C, Tuomi T, Taskinen MR, Groop L (1999) Mutation in the HNF-4 alpha gene affects insulin secretion and triglyceride metabolism. Diabetes 48:423–425PubMedGoogle Scholar
  82. 82.
    Hansen SK, Parrizas M, Jensen ML, Pruhova S, Ek J, Boj SF, Johansen A, Maestro MA, Rivera F, Eiberg H, Andel M, Lebl J, Pedersen O, Ferrer J, Hansen T (2002) Genetic evidence that HNF-1alpha-dependent transcriptional control of HNF-4alpha is essential for human pancreatic beta cell function. J Clin Invest 110:827–833PubMedGoogle Scholar
  83. 83.
    Thomas H, Jaschkowitz K, Bulman M, Frayling TM, Mitchell SMS, Roosen S, Lingott-Frieg A, Tack CJ, Ellard S, Ryffel GU, Hattersley AT (2001) A distant upstream promoter of the HNF-4alpha gene connects the transcription factors involved in maturity-onset diabetes of the young. Hum Mol Genet 10:2089–2097PubMedGoogle Scholar
  84. 84.
    Gupta RK, Vatamaniuk MZ, Lee CS, Flaschen RC, Fulmer JT, Matschinsky FM, Duncan SA, Kaestner KH (2005) The MODY1 gene HNF-4alpha regulates selected genes involved in insulin secretion. J Clin Invest 115:1006–1015PubMedGoogle Scholar
  85. 85.
    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, Pedersen O, Polonsky KS, Turner RC, Velho G, Chevre J-C, Froguel P, Bell GI (1996) Mutations in the hepatic nuclear factor 1 alpha gene in maturity-onset diabetes of the young (MODY3). Nature 384:455–458PubMedGoogle Scholar
  86. 86.
    Frayling T, Bulman MP, Ellard S, Appleton M, Dronsfield M, Mackie A, Baird J, Kaisaki P, Yamagata K, Bell G, Bain S, Hattersley A (1997) Mutations in the Hepatocyte Nuclear Factor 1 Alpha gene are a common cause of maturity-onset diabetes of the young in the United Kingdom. Diabetes 46:720–725PubMedGoogle Scholar
  87. 87.
    Lehto M, Tuomi T, Mahtani MM, Widen E, Forsblom C, Sarelin L, Gullstrom M, Isomaa B, Lehtovirta M, Hyrkko A, Kanninen T, Orho M, Manley S, Turner RC, Brettin T, Kirby A, Thomas J, Duyk G, Lander E, Taskinen M-R, Groop L (1997) Characterization of the MODY3 phenotype. Early-onset diabetes caused by an insulin secretion defect. J Clin Invest 99:582–591PubMedGoogle Scholar
  88. 88.
    Harries LW, Ellard S, Stride A, Morgan NG, Hattersley AT (2006) Isomers of the TCF1 gene encoding hepatocyte nuclear factor-1 alpha show differential expression in the pancreas and define the relationship between mutation position and clinical phenotype in monogenic diabetes. Hum Mol Genet 15:2216–2224PubMedGoogle Scholar
  89. 89.
    Stride A, Ellard S, Clark P, Shakespeare L, Salzmann M, Shepherd M, Hattersley AT (2005) Beta-cell dysfunction, insulin sensitivity, and glycosuria precede diabetes in hepatocyte nuclear factor-1alpha mutation carriers. Diabetes Care 28:1751–1756PubMedGoogle Scholar
  90. 90.
    Menzel R, Kaisaki PJ, Rjasanowski I, Heinke P, Kerner W, Menzel S (1998) A low renal threshold for glucose in diabetic patients with a mutation in the hepatocyte nuclear factor-1alpha (HNF-1alpha) gene. Diabet Med 15:816–820PubMedGoogle Scholar
  91. 91.
    Bingham C, Ellard S, Nicholls AJ, Pennock CA, Allen J, James AJ, Satchell SC, Salzmann MB, Hattersley AT (2001) The generalized aminoaciduria seen in patients with hepatocyte nuclear factor-1alpha mutations is a feature of all patients with diabetes and is associated with glucosuria. Diabetes 50:2047–2052PubMedGoogle Scholar
  92. 92.
    Byrne MM, Sturis J, Menzel S, Yamagata K, Fajans SS, Dronsfield MJ, Bain SC, Hattersley AT, Velho G, Froguel P, Bell GI, Polonsky KS (1996) Altered insulin secretory responses to glucose in diabetic and nondiabetic subjects with mutations in the diabetes susceptibility gene MODY3 on Chromosome 12. Diabetes 45:1503–1510PubMedGoogle Scholar
  93. 93.
    Hattersley AT (1998) Maturity-onset diabetes of the young: Clinical heterogeneity explained by genetic hetergeneity. Diabet Med 15:15–24PubMedGoogle Scholar
  94. 94.
    Velho G, Vaxillaire M, Boccio V, Charpentier G, Froguel P (1996) Diabetes complications in NIDDM kindreds linked to the MODY3 locus on chromosome 12q. Diabetes Care 19:915–919PubMedGoogle Scholar
  95. 95.
    Isomaa B, Henricsson M, Lehto M, Forsblom C, Karanko S, Sarelin L, Haggblom M, Groop L (1998) Chronic diabetic complications in patients with MODY3 diabetes. Diabetologia 41:467–473PubMedGoogle Scholar
  96. 96.
    Sovik O, Njolstad P, Folling I, Sagen J, Cockburn BN, Bell GI (1998) Hyperexcitability to sulphonylurea in MODY3. Diabetologia 41:607–608PubMedGoogle Scholar
  97. 97.
    Pearson ER, Liddell WG, Shepherd M, Corrall RJ, Hattersley AT (2000) Sensitivity to sulphonylureas in patients with hepatocyte nuclear factor 1 alpha gene mutations: evidence for pharmacogenetics in diabetes. Diabet Med 17:543–545PubMedGoogle Scholar
  98. 98.
    Pearson ER, Starkey BJ, Powell RJ, Gribble FM, Clark PM, Hattersley AT (2003) Genetic aetiology of hyperglycaemia determines response to treatment in diabetes. Lancet 362:1275–1281PubMedGoogle Scholar
  99. 99.
    Yamagata K, Nammo T, Moriwaki M, Ihara A, Iizuka K, Yang Q, Satoh T, Li M, Uenaka R, Okita K, Iwahashi H, Zhu Q, Cao Y, Imagawa A, Tochino Y, Hanafusa T, Miyagawa J, Matsuzawa Y (2002) Overexpression of dominant-negative mutant hepatocyte nuclear fctor-1 alpha in pancreatic beta-cells causes abnormal islet architecture with decreased expression of E-cadherin, reduced beta-cell proliferation, and diabetes. Diabetes 51:114–123PubMedGoogle Scholar
  100. 100.
    Harries LW, Ellard S, Jones RW, Hattersley AT, Bingham C (2004) Abnormal splicing of hepatocyte nuclear factor-1 beta in the renal cysts and diabetes syndrome. Diabetologia 47:937–942PubMedGoogle Scholar
  101. 101.
    Wang H, Maechler P, Hagenfeldt KA, Wollheim CB (1998) Dominant-negative suppression of HNF-1alpha function results in defective insulin gene transcription and impaired metabolism-secretion coupling in a pancreatic beta-cell line. EMBO J 17:6701–6713PubMedGoogle Scholar
  102. 102.
    Wang H, Antinozzi PA, Hagenfeldt KA, Maechler P, Wollheim CB (2000) Molecular targets of a human HNF1 alpha mutation responsible for pancreatic beta-cell dysfunction. EMBO J 19:4257–4264PubMedGoogle Scholar
  103. 103.
    Shih DQ, Screenan S, Munoz KN, Philipson L, Pontoglio M, Yaniv M, Polonsky KS, Stoffel M (2001) Loss of HNF-1alpha function in mice leads to abnormal expression of genes involved in pancreatic islet development and metabolism. Diabetes 50:2472–2480PubMedGoogle Scholar
  104. 104.
    Wobser H, Dumann H, Kogel D, Wang H, Reimertz C, Wollheim CB, Byrne MM, Prehn JH (2001) Dominant-negative suppression of HNF-1alpha results in mitochondrial dysfunction, INS-1 cell apoptosis, and Increased sensitivity to ceramide-, but not to high glucose-induced cell death. J Biol Chem 27:27Google Scholar
  105. 105.
    Pontoglio M, Prie D, Cheret C, Doyen A, Lero C, Froguel P, Velho G, Yaniv M, Friedlander G (2000) HNF1 alpha controls renal glucose reabsorption in mouse and man. EMBO Rep 1:359–365PubMedGoogle Scholar
  106. 106.
    Gragnoli C, Stanojevic V, Gorini A, Von Preussenthal GM, Thomas MK, Habener JF (2005) IPF-1/MODY4 gene missense mutation in an Italian family with type 2 and gestational diabetes. Metabolism 54:983–988PubMedGoogle Scholar
  107. 107.
    Ahlgren U, Jonsson J, Jonsson L, Simu K, Edlund H (1998) beta-cell-specific inactivation of the mouse Ipf1/Pdx1 gene results in loss of the beta-cell phenotype and maturity-onset diabetes. Genes Dev 12:1763–1768PubMedGoogle Scholar
  108. 108.
    Horikawa Y, Iwasaki N, Hara M, Furuta H, Hinokio Y, Cockburn B, Lindner T, Yamagata K, Ogata M, Tomonaga O, Kuroki H, Kasahar T, Iwamoto Y, Bell GI (1997) Mutation in hepatocyte nuclear factor-1b gene (TCF2) associated with MODY. Nat Genet 17:384–385PubMedGoogle Scholar
  109. 109.
    Bingham C, Hattersley AT (2004) Renal cysts and diabetes syndrome resulting from mutations in hepatocyte nuclear factor-1beta. Nephrol Dial Transplant 19:2703–2708PubMedGoogle Scholar
  110. 110.
    Edghill EL, Bingham C, Ellard S, Hattersley AT (2006) Mutations in hepatocyte nuclear factor-1beta and their related phenotypes. J Med Genet 43:84–90PubMedGoogle Scholar
  111. 111.
    Bellanne-Chantelot C, Clauin S, Chauveau D, Collin P, Daumont M, Douillard C, Dubois-Laforgue D, Dusselier L, Gautier JF, Jadoul M, Laloi-Michelin M, Jacquesson L, Larger E, Louis J, Nicolino M, Subra JF, Wilhem JM, Young J, Velho G, Timsit J (2005) Large genomic rearrangements in the hepatocyte nuclear factor-1beta (TCF2) gene are the most frequent cause of maturity-onset diabetes of the young type 5. Diabetes 54:3126–3132PubMedGoogle Scholar
  112. 112.
    Ulinski T, Lescure S, Beaufils S, Guigonis V, Decramer S, Morin D, Clauin S, Deschenes G, Bouissou F, Bensman A, Bellanne-Chantelot C (2006) Renal phenotypes related to hepatocyte nuclear factor-1beta (TCF2) mutations in a pediatric cohort. J Am Soc Nephrol 17:497–503PubMedGoogle Scholar
  113. 113.
    Pearson ER, Badman MK, Lockwood CR, Clark PM, Ellard S, Bingham C, Hattersley AT (2004) Contrasting diabetes phenotypes associated with hepatocyte nuclear factor-1alpha and-1beta mutations. Diabetes Care 27:1102–1107PubMedGoogle Scholar
  114. 114.
    Nishigori H, Yamada S, Kohama T, Tomura H, Sho K, Horikawa Y, Bell GI, Takeuchi T, Takeda J (1998) Frameshift mutation, A263fsinsGG, in the hepatocyte nuclear factor-1 beta gene associated with diabetes and renal dysfunction. Diabetes 47:1354–1355PubMedGoogle Scholar
  115. 115.
    Bingham C, Bulman MP, Ellard S, Allen LI, Lipkin GW, Hoff WG, Woolf AS, Rizzoni G, Novelli G, Nicholls AJ, Hattersley AT (2001) Mutations in the hepatocyte nuclear factor-1beta gene are associated with familial hypoplastic glomerulocystic kidney disease. Am J Hum Genet 68:219–224PubMedGoogle Scholar
  116. 116.
    Carbone I, Cotellessa M, Barella C, Minetti C, Ghiggeri GM, Caridi G, Perfumo F, Lorini R (2002) A novel hepatocyte nuclear factor-1beta (MODY-5) gene mutation in an Italian family with renal dysfunctions and early-onset diabetes. Diabetologia 45:153–154PubMedGoogle Scholar
  117. 117.
    Lindner TH, Njolstad PR, Horikawa Y, Bostad L, Bell GI, Sovik O (1999) A novel syndrome of diabetes mellitus, renal dysfunction and genital malformation associated with a partial deletion of the pseudo-POU domain of hepatocyte nuclear factor-1beta. Hum Mol Genet 8:2001–2008PubMedGoogle Scholar
  118. 118.
    Bellanne-Chantelot C, Chauveau D, Gautier JF, Dubois-Laforgue D, Clauin S, Beaufils S, Wilhelm JM, Boitard C, Noel LH, Velho G, Timsit J (2004) Clinical spectrum associated with hepatocyte nuclear factor-1beta mutations. Ann Intern Med 140:510–517PubMedGoogle Scholar
  119. 119.
    Montoli A, Colussi G, Massa O, Caccia R, Rizzoni G, Civati G, Barbetti F (2002) Renal cysts and diabetes syndrome linked to mutations of the hepatocyte nuclear factor-1 beta gene: description of a new family with associated liver involvement. Am J Kidney Dis 40:397–402PubMedGoogle Scholar
  120. 120.
    Kitanaka S, Miki Y, Hayashi Y, Igarashi T (2004) Promoter-specific repression of hepatocyte nuclear factor (HNF)-1 beta and HNF-1 alpha transcriptional activity by an HNF-1 beta missense mutant associated with Type 5 maturity-onset diabetes of the young with hepatic and biliary manifestations. J Clin Endocrinol Metab 89:1369–1378PubMedGoogle Scholar
  121. 121.
    Barbacci E, Reber M, Ott M-O, Breillat C, Huetz F, Cereghini S (1999) Variant hepatocyte nuclear factor1 is required for visceral endoderm specification. Development 126:4795–4805PubMedGoogle Scholar
  122. 122.
    Coffinier C, Thepot D, Babinet C, Yaniv M, Barra J (1999) Essential role for the homeoprotein vHNF1/HNF1beta in visceral endoderm differentiation. Development 126:4785–4794PubMedGoogle Scholar
  123. 123.
    Poll AV, Pierreux CE, Lokmane L, Haumaitre C, Achouri Y, Jacquemin P, Rousseau GG, Cereghini S, Lemaigre FP (2006) A vHNF1/TCF2-HNF6 cascade regulates the transcription factor network that controls generation of pancreatic precursor cells. Diabetes 55:61–69PubMedGoogle Scholar
  124. 124.
    Igarashi P, Shao X, McNally BT, Hiesberger T (2005) Roles of HNF-1beta in kidney development and congenital cystic diseases. Kidney Int 68:1944–1947PubMedGoogle Scholar
  125. 125.
    Hart TC, Gorry MC, Hart PS, Woodard AS, Shihabi Z, Sandhu J, Shirts B, Xu L, Zhu H, Barmada MM, Bleyer AJ (2002) Mutations of the UMOD gene are responsible for medullary cystic kidney disease 2 and familial juvenile hyperuricaemic nephropathy. J Med Genet 39:882–892PubMedGoogle Scholar
  126. 126.
    Ward CJ, Hogan MC, Rossetti S, Walker D, Sneddon T, Wang X, Kubly V, Cunningham JM, Bacallao R, Ishibashi M, Milliner DS, Torres VE, Harris PC (2002) The gene mutated in autosomal recessive polycystic kidney disease encodes a large, receptorlike protein. Nat Genet 30:259–269PubMedGoogle Scholar
  127. 127.
    Malecki MT, Jhala US, Antonellis A, Fields L, Doria A, Orban T, Saad M, Warram JH, Montminy M, Krolewski AS (1999) Mutations in NEUROD1 are associated with the development of Type 2 diabetes mellitus. Nat Genet 23:323–328PubMedGoogle Scholar
  128. 128.
    Kristinsson SY, Thorolfsdottir ET, Talseth B, Steingrimsson E, Thorsson AV, Helgason T, Hreidarsson AB, Arngrimsson R (2001) MODY in Iceland is associated with mutations in HNF-1alpha and a novel mutation in NeuroD1. Diabetologia 44:2098–2103PubMedGoogle Scholar
  129. 129.
    Naya FJ, Stellrecht CM, Tsai MJ (1995) Tissue-specific regulation of the insulin gene by a novel basic helix-loop-helix transcription factor. Genes Dev 9:1009–1019PubMedGoogle Scholar
  130. 130.
    Naya FJ, Huang H-P, Qiu Y, Mutoh H, DeMayo FJ, Leiter AB, Tsai M-J (1997) Diabetes, defective pancreatic morphogenesis, and abnormal enteroendocrine differentiation in BETA2/NeuroD1-deficient mice. Genes Dev 11:2323–2334PubMedGoogle Scholar
  131. 131.
    Qiu Y, Sharma A, Stein R (1998) p300 mediates transcriptional stimulation by the basic helix-loop-helix activators of the insulin gene. Mol Cell Biol 18:2957–2964PubMedGoogle Scholar
  132. 132.
    Sharma A, Moore M, Marcora E, Lee JE, Qiu Y, Samaras S, Stein R (1999) The NeuroD1/BETA2 sequences essential for insulin gene transcription colocalize with those necessary for neurogenesis and p300/CREB binding protein binding. Mol Cell Biol 19:704–713PubMedGoogle Scholar
  133. 133.
    Raeder H, Johansson S, Holm PI, Haldorsen IS, Mas E, Sbarra V, Nermoen I, Eide SA, Grevle L, Bjorkhaug L, Sagen JV, Aksnes L, Souik O, Lombardo D, Molven A, Njolstad PR (2006) Mutations in the CEL VNTR cause a syndrome of diabetes and pancreatic exocrine dysfunction. Nat Genetics 38:54–62Google Scholar
  134. 134.
    Lombardo D (2001) Bile salt-dependent lipase: its pathophysiological implications. Biochim Biophys Acta 1533:1–28PubMedGoogle Scholar
  135. 135.
    Hui DY, Howles PN (2002) Carboxyl ester lipase: structure-function relationship and physiological role in lipoprotein metabolism and atherosclerosis. J Lipid Res 43:2017–2030PubMedGoogle Scholar
  136. 136.
    Frayling TM, Evans JC, Bulman MP, Pearson E, Allen L, Owen K, Bingham C, Hannemann M, Shepherd M, Ellard S, Hattersley AT (2001) beta-cell genes and diabetes: molecular and clinical characterization of mutations in transcription factors. Diabetes 50:S94–S100PubMedGoogle Scholar
  137. 137.
    Hattersley AT (2006) Beyond the beta cell in diabetes. Nat Genet 38:12–13PubMedGoogle Scholar
  138. 138.
    Fajans SS, Bell GI (2006) Phenotypic heterogeneity between different mutations of MODY subtypes and within MODY pedigrees. Diabetologia 49:1106–1108PubMedGoogle Scholar
  139. 139.
    Servitja JM, Ferrer J (2004) Transcriptional networks controlling pancreatic development and beta cell function. Diabetologia 47:597–613PubMedGoogle Scholar
  140. 140.
    Hattersley AT, Pearson ER (2006) Minireview: pharmacogenetics and beyond: the interaction of therapeutic response, beta-cell physiology, and genetics in diabetes. Endocrinology 147:2657–2663PubMedGoogle Scholar

Copyright information

© Springer 2008

Authors and Affiliations

  • Emma L. Edghill
    • 1
  • Andrew T. Hattersley
    • 1
  1. 1.Institute of Biomedical and Clinical SciencePeninsula Medical SchoolExeter, DevonUK

Personalised recommendations