Clinical Consequences of Defects in β-Cell Genes

  • Julie C. Evans
  • Timothy M. Frayling
  • Andrew T. Hattersley
Chapter
Part of the Endocrine Updates book series (ENDO, volume 11)

Abstract

Genes critical for β-cell function have been identified by the genetic analysis of families with maturity onset diabetes of the young (MODY). The clinical description of MODY families by Fajans and Tattersall (1,2) and the development of appropriate molecular genetic techniques were both critical in the definition of these genes. In this chapter, we describe the clinical and physiological features of patients with known defects in β-cell genes. This has led to the demonstration of previously un-recognized heterogeneity in clinically defined MODY. In addition, it has given fascinating insights into the role of the genes in the normal β-cell both in post-natal and foetal life.

Keywords

Codon Pyruvate Proteinuria Hyperglycemia Hypoglycemia 

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References

  1. 1.
    Tattersall RB. Mild familial diabetes with dominant inheritance. Q J Med 1974;43:339–357.PubMedGoogle Scholar
  2. 2.
    Tattersall RB, Fajans SS. A difference between the inheritance of classical juvenile-onset and maturity-onset type diabetes of young people. Diabetes 1975;24:44–53.PubMedCrossRefGoogle Scholar
  3. 3.
    Froguel P, Vaxillaire M, Sun F, et al. Close linkage of glucokinase locus on chromosome 7p to early-onset non-insulin-dependent diabetes mellitus. Nature 1992;356:162–4.PubMedCrossRefGoogle Scholar
  4. 4.
    Hattersley AT, Turner RC, Permutt MA, et al. Linkage of type 2 diabetes to the glucokinase gene. Lancet 1992;339:1307–10.PubMedCrossRefGoogle Scholar
  5. 5.
    Yamagata K, Fureta H, Oda N, et al. Mutations in the hepatocyte nuclear factor 4 alpha gene in maturity-onset diabetes of the young (MODY1). Nature 1996;384:458–460.PubMedCrossRefGoogle Scholar
  6. 6.
    Yamagata K, Oda N, Kaisaki PJ, et al. Mutations in the hepatic nuclear factor 1 alpha gene in maturity-onset diabetes of the young (MODY3). Nature 1996;384:455–458.PubMedCrossRefGoogle Scholar
  7. 7.
    Stoffers DA, Ferrer J, Clarke WL, Habener JF. Early-onset type-II diabetes mellitus (MODY4) linked to IPFI. Nature Genetics 1997;17:138–139.PubMedCrossRefGoogle Scholar
  8. 8.
    Horikawa Y, Iwasaki N, Hara M, et al. Mutation in hepatocyte nuclear factor-lb gene (TCF2) associated with MODY. Nature Genetics 1997;17:384–5.PubMedCrossRefGoogle Scholar
  9. 9.
    Meglasson MD, Matschinsky FM. Pancreatic islet glucose metabolism and regulation of insulin secretion. Diabetes/Metabolism Reviews 1986;2:163–214.PubMedCrossRefGoogle Scholar
  10. 10.
    Matschinsky FM. Glucokinase as glucose sensor and metabolic signal generator in pancreatic 13-cell and hepatocytes. Diabetes 1990;30:647–752.CrossRefGoogle Scholar
  11. 11.
    Vionnet N, Stoffel M, Takeda J, et al. Nonsense mutation in the glucokinase gene causes early-onset non-insulin-dependent diabetes mellitus. Nature 1992;356:721–2.PubMedCrossRefGoogle Scholar
  12. 12.
    Stoffel M, Froguel P, Takeda J, et al. Human glucokinase gene: isolation, characterization, and identification of two missense mutations linked to early-onset non-insulin-dependent diabetes. Proc Natl Acad Sci USA 1992;89:7698–702.PubMedCrossRefGoogle Scholar
  13. 13.
    Stoffel M, Patel P, Lo YM, et al. Missense glucokinase mutation in maturity-onset diabetes of the young and mutation screening in late-onset diabetes. Nature Genetics 1992;2:153–6.PubMedCrossRefGoogle Scholar
  14. 14.
    Tanizawa Y, Matsutani A, Chiu KC, Permutt MA. Human glucokinase gene: isolation, structural characterization, and identification of a microsatellite repeat polymorphism. Molecular Endocrinology 1992;6:1070–81.PubMedCrossRefGoogle Scholar
  15. 15.
    Sun F, Knebelmann B, Pueyo ME, et al. Deletion of the donor splice site of intron 4 in the glucokinase gene causes maturity-onset diabetes of the young. J Clin Invest 1993;92:1174–80.PubMedCrossRefGoogle Scholar
  16. 16.
    Stoffel M, Bell KL, Blackburn CL, et al. Identification of glucokinase mutations in subjects with gestational diabetes mellitus. Diabetes 1993;42:937–940.PubMedCrossRefGoogle Scholar
  17. 17.
    Shimada F, Makino H, Hashimoto N, et al. Type 2 (non-insulin-dependent) diabetes mellitus associated with a mutation of the glucokinase gene in a Japanese family. Diabetologia 1993;36:4337.CrossRefGoogle Scholar
  18. 18.
    Froguel P, Zouali H, Vionnet N, et al. Familial hyperglycemia due to mutations in glucokinase. Definition of a subtype of diabetes mellitus. N Engl J Med 1993;328:697–702.PubMedCrossRefGoogle Scholar
  19. 19.
    Hager J, Blanche H, Sun F, et al. Six mutations in the glucokinase gene identified in MODY by using a nonradioactive sensitive screening technique. Diabetes 1994;43:730–3.PubMedCrossRefGoogle Scholar
  20. 20.
    Eto K, Sakura H, Shimokawa K, et al. Sequence variations of the glucokinase gene in Japanese subjects with NIDDM. Diabetes 1993;42:1133–7.PubMedCrossRefGoogle Scholar
  21. 21.
    Velho G, Blanche H, Vaxillaire M, et al. Identification of 14 new glucokinase mutations and description of the clinical profile of 42 MODY-2 families. Diabetologia 1997;40:217–224.PubMedCrossRefGoogle Scholar
  22. 22.
    Hattersley AT, Beards F, Ballantyne E, Appleton M, Harvey R, Ellard S. Mutations in the glucokinase gene of the fetus result in reduced birth weight. Nat Genet 1998;19:268–270.PubMedCrossRefGoogle Scholar
  23. 23.
    Gidh-Jain M, Takeda J, Xu LZ, et al. Glucokinase mutations associated with non-insulin-dependent (type 2) diabetes mellitus have decreased enzymatic activity: implications for structure/function relationships. Proc Natl Acad Sci USA 1993;90:1932–6.PubMedCrossRefGoogle Scholar
  24. 24.
    Takeda J, Gidh-Jain M, Zhong Xu L, et al. Structure/Function Studies of Human Beta-cell Glucokinase. J Biol Chem 1993;20:15200–15204.Google Scholar
  25. 25.
    Pilkis SJ, Weber IT, Harrison RW, Bell GI. Glucokinase: structural analysis of a protein involved in susceptibility to diabetes. [Review]. J Biol Chem 1994;269:21925–8.PubMedGoogle Scholar
  26. 26.
    Glaser B, Kesavan P, Heyman M, et al. Familial hyperinsulinism caused by an activating glucokinase mutation. N Engl J Med 1998;338:226–230.PubMedCrossRefGoogle Scholar
  27. 27.
    Dow E, Gelding SV, Skinner E, et al. Genetic analysis of glucokinase and the chromosome 20 diabetes susceptibility locus in families with type 2 diabetes. Diabetic Medicine 1994;11:856–61.PubMedCrossRefGoogle Scholar
  28. 28.
    Zhang Y, Warren-Perry MG, Saker Pi, et al. Candidate genes study in pedigrees with maturity-onset diabetes of the young not linked with glucokinase. Diabetologia 1995;38:1055–1060.PubMedCrossRefGoogle Scholar
  29. 29.
    Hattersley AT. Maturity-onset diabetes of the young: clinical heterogeneity explained by genetic heterogeneity. Diab Med 1998;15:15–24.CrossRefGoogle Scholar
  30. 30.
    Katagiri H, Asano T, Ishihara H, et al. Nonsense mutation of glucokinase gene in late-onset noninsulin-dependent diabetes mellitus. Lancet 1992;340:1316–7.PubMedCrossRefGoogle Scholar
  31. 31.
    Zouali H, Vaxillaire M, Lesage S, et al. Linkage analysis and molecular scanning of glucokinase gene in NIDDM families. Diabetes 1993;42:1238–45.PubMedCrossRefGoogle Scholar
  32. 32.
    Saker PJ, Hattersley AT, Barrow B, et al. High prevalence of a missense mutation of the glucokinase gene in gestational diabetic patients due to a founder-effect in a local population. Diabetologia 1996;39:1325–1328.PubMedCrossRefGoogle Scholar
  33. 33.
    Hattersley AT, Turner RC. Mutations of the glucokinase gene and type 2 diabetes. [Review]. Quarterly Journal of Medicine 1993;86:227–32.PubMedGoogle Scholar
  34. 34.
    Hattersley AT. Glucokinase mutations and Type 2 diabetes. In: Lightman S, ed. Horizons in Medicine. Vol. 7. Bristol: Blackwell Science, 1996:440–449.Google Scholar
  35. 35.
    O’Rahilly S, Hattersley A, Vaag A, Gray H. Insulin resistance as the major cause of impaired glucose tolerance: a self-fulfilling prophesy? Lancet 1994;344:585–9.PubMedCrossRefGoogle Scholar
  36. 36.
    Page RC, Hattersley AT, Levy JC, et al. Clinical characteristics of subjects with a missense mutation in glucokinase. Diab Med 1995;12:209–17.CrossRefGoogle Scholar
  37. 37.
    Velho G, Froguel P, Clement K, et al. Primary pancreatic beta-cell secretory defect caused by mutations in glucokinase gene in kindreds of maturity onset diabetes of the young. Lancet 1992;340:444–8.PubMedCrossRefGoogle Scholar
  38. 38.
    Byrne MM, Sturis J, Clement K, et al. Insulin secretory abnormalities in subjects with hyperglycemia due to glucokinase mutations. J Clin Invest 1994;93:1120–30.PubMedCrossRefGoogle Scholar
  39. 39.
    Velho G, Hwang J-H, Petersen K, et al. Altered hepatic glycogen synthesis in glucokinase deficient subjects [abstract]. Diabetalogia 1994;37:A131.Google Scholar
  40. 40.
    Clement K, Pueyo ME, Vaxillaire M, et al. Assessment of insulin sensitivity in glucokinasedeficient subjects. Diabetologia 1996;39:82–90.PubMedGoogle Scholar
  41. 41.
    Frain M, Swart G, Monaci P, et al. The liver-specific transcription factor LF-B i contains a highly diverged homeobox DNA binding domain. Cell 1989;59:145–157.PubMedCrossRefGoogle Scholar
  42. 42.
    Mendel DB, Hansen LP, Graves MK, Conley PB, Crabtree GR. HNF-la and HNF-lb (vHNF-1) share dimerisation and homeo domains, but not activation domains, and form heterodimers in vitro. Genes and Development 1991;5:1042–1056.PubMedCrossRefGoogle Scholar
  43. 43.
    Miquerol L, Lopez S, Cartier N, Tulliez M, Raymondjean M, Kahn A. Expression of the L-type pyruvate kinase gene and the hepatocyte nuclear factor 4 transcription factor in exocrine and endocrine pancreas. J Biol Chem 1994;269:8944–8951.PubMedGoogle Scholar
  44. 44.
    Vaxillaire M, Boccio V, Philippi A, et al. A gene for maturity onset diabetes of the young (MODY) maps to chromosome 12q. Nat Gen 1995;9:418–23.CrossRefGoogle Scholar
  45. 45.
    Frayling T, Bulman MP, Ellard S, et al. 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 1997;46:720–725.PubMedCrossRefGoogle Scholar
  46. 46.
    Kaisaki PJ, Menzel S, Lindner T, et al. Mutations in the Hepatocyte Nuclear Factor 1 a Gene in MODY and Early-onset NIDDM: Evidence for a Mutational Hotspot in Exon 4. Diabetes 1997;45:528–535.CrossRefGoogle Scholar
  47. 47.
    Vaxillaire M, Rouard M, Yamagata K, et al. Identification of nine novel mutations in the hepatocyte nuclear factor 1 alpha gene associated with maturity onset diabetes of the young (MODY3). Human Molecular Genetics 1997;6:583–586.PubMedCrossRefGoogle Scholar
  48. 48.
    Hansen T, Eiberg H, Rouard M, et al. Novel MODY3 Mutations in the Hepatic Nuclear Factor-la Gene. Diabetes 1997;46:726–730.PubMedCrossRefGoogle Scholar
  49. 49.
    Gragnoli C, Lindner T, Marozzi G, Andreani D. Disruption of the HNF-4a promoter in an Italian family with MODY. Diabetologia 1997;40:A7.CrossRefGoogle Scholar
  50. 50.
    Glucksmann MA, Lehto M, Tayber O, et al. Novel mutations and a mutational hotspot in the MODY3 gene. Diabetes 1997;46:1081–1086.PubMedCrossRefGoogle Scholar
  51. 51.
    Iwasaki N, Oda N, Ogata M, et al. Mutations in the Hepatocyte Nuclear Factor-la/MODY3 gene in Japanese subjects with early-and late-onset NIDDM. Diabetes 1997;46:1504–1508.PubMedCrossRefGoogle Scholar
  52. 52.
    Velho G, Vaxillaire M, Boccio V, Charpentier G, Froguel P. Diabetes complications in NIDDM kindreds linked to the MODY3 locus on chromosome 12q. Diabetes Care 1996;19:915–919.PubMedCrossRefGoogle Scholar
  53. 53.
    Isomaa B, Henricsson M, Lehto M, et al. Chronic diabetic complications in patients with MODY3 diabetes. Diabetologia 1998;41:467–473.PubMedCrossRefGoogle Scholar
  54. 54.
    Sovik O, Njolstad P, Foiling I, Sagen J, Cockburn BN, Bell GI. Hyperexcitability to sulphonylurea in MODY3. Diabetologia 1998;41(5):607–8.PubMedCrossRefGoogle Scholar
  55. 55.
    Byrne MM, Sturis J, Menzel S, et al. Altered insulin secretory responses to glucose in diabetic and nondiabetic subjects with mutations in the diabetes susceptibility gene MODY3 on Chromosome 12. Diabetes 1996;45:1503–1510.PubMedCrossRefGoogle Scholar
  56. 56.
    Bell GI, Xiang KS, Newman MV, et al. Gene for non-insulin-dependent diabetes mellitus (maturity-onset diabetes of the young subtype) is linked to DNA polymorphism on human chromosome 20q. Proc Natl Acad Sci USA 1991;88:1484–8.PubMedCrossRefGoogle Scholar
  57. 57.
    Bulman M, Dronsfield MJ, Frayling T, et al. A missense mutation in the hepatocyte nuclear factor 4 alpha gene in a UK pedigree with maturity-onset diabetes of the young. Diabetologia 1997;40:859–863.PubMedCrossRefGoogle Scholar
  58. 58.
    Lindner T, Gragnoli C, Furuta H, et al. Hepatic function in a family with a nonsense mutation (R154X) in the Hepatocyte Nuclear Factor-4a/MODYI gene. J Clin Invest 1997;100:1400–1405.PubMedCrossRefGoogle Scholar
  59. 59.
    Moller AM, Urhammer SA, Dalgaard LT, et al. Studies of the genetic variability of the coding region of the hepatocyte nuclear factor-4a in Caucasians with maturity onset NIDDM. Diabetologia 1997;40:980–983.PubMedCrossRefGoogle Scholar
  60. 60.
    Furuta H, Iwasaki N, Oda N, et al. Organization and partial sequence of the hepatocyte nuclear factor-4a/MODY1 gene and identification of a missense mutation R127W, in a Japanese family with MODY. Diabetes 1997;46:1652–7.PubMedCrossRefGoogle Scholar
  61. 61.
    Hani E, Suaud L, Boutin P, et al. A missense mutation in hepatocyte nuclear factor-4 alpha, resulting in a reduced transactivation activity, in human late-onset non-insulin-dependent diabetes mellitus. J Clin Invest 1998;101:521–526.PubMedCrossRefGoogle Scholar
  62. 62.
    Byrne MM, Sturis J, Fajans SS, et al. Altered insulin secretory responses to glucose in subjects with a mutation in the MODY1 gene on chromosome 20. Diabetes 1995;44:699–704.PubMedCrossRefGoogle Scholar
  63. 63.
    Marshak S, Totary H, Cerasi E, Melloul D. Purification of the ß-cell glucose-sensitive factor that transactivates the insulin gene differentially in normal and transformed islet cells. Proc Natl Acad Sci USA 1996;93:15057–15062.PubMedCrossRefGoogle Scholar
  64. 64.
    Macfarlane WM, Read ML, Gilligan M, Bujalska 1, Docherty K. Glucose modulates the binding activity of the ß-cell transcription factor IUF1 in a phosphorylation-dependent manner. Biochem J 1993;303:625–631.Google Scholar
  65. 65.
    Johnsson JL, Carlsson T, Edlund T, Edlund H. Insulin promoter factor 1 is required for pancreas development in mice. Nature 1994;371:606–609.CrossRefGoogle Scholar
  66. 66.
    Inoue H, Riggs AC, Tanizawa Y, et al. Isolation, characterization, and chromosomal mapping of the human insulin promoter factor 1 (IPF-1) gene. Diabetes 1996;45:789–794.PubMedCrossRefGoogle Scholar
  67. 67.
    Stoffers DA, Zinkin NT, Stanojevic V, Clarke WL, Habener JF. Pancreatic agenesis attributable to a single nucleotide deletion in the human IPF1 gene coding sequence. Nat Gen 1997;15:106–110.CrossRefGoogle Scholar
  68. 68.
    Ahlgren U, Jonsson J, Jonsson L, Simu K, Edlund H. Beta-cell-specific inactivation of the mouse Ipfl/Pdxl gene results in loss of the beta-cell phenotype and maturity onset diabetes. Genes Dev 1998;12:1763–8.PubMedCrossRefGoogle Scholar
  69. 69.
    Nishigori H, Yamada S, Kohama T, et al. Frameshift mutation, A263fsinsGG, in the hepatocyte nuclear factor-1 beta gene associated with diabetes and renal dysfunction. Diabetes 1998;47:1354–1355.PubMedCrossRefGoogle Scholar
  70. 70.
    Lindner TH, Nj, Horikawa Y, Bostad L, Bell GI, Vik. O. 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-lbeta. Hum Mol Genet 1999;8:2001–2008.Google Scholar
  71. 71.
    Macfarlane W, Frayling T, Ellard S, et al. Missense mutations in the Insulin Promoter Factor I (IPF-1) gene predispose to Type 2 diabetes. J Clin Invest 1999;104:R33–R39.PubMedCrossRefGoogle Scholar
  72. 72.
    Mahtani M, Widen E, Lehto M, et al. Mapping of a gene for type 2 diabetes associated with an insulin secretion defect by a genome scan in Finnish families. Nat Gen 1996;14:90–94.CrossRefGoogle Scholar
  73. 73.
    Ji L, Malecki M, Warram HJ, Yang Y, Rich SS, Krolewski AS. New susceptibility locus for NIDDM is localized to human chromosome 20q. Diabetes 1997;46:876–881.PubMedCrossRefGoogle Scholar
  74. 74.
    Bowden WD, Sale M, Howard TD, et al. Linkage of genetic markers on human chromosomes 20 and 12 to NIDDM in Caucasian sib pairs with a history of diabetic nephropathy. Diabetes 1997;46:882–886.PubMedCrossRefGoogle Scholar
  75. 75.
    Zouali H, Hani EH, Philippi A, et al. A susceptibility locus for early-onset non-insulin dependent (type 2) diabetes mellitus maps to chromosome 20q, proximal to the phosphoenolpyruvate carboxykinase gene. Human Molecular Genetics 1997;6:1401–1408.PubMedCrossRefGoogle Scholar
  76. 76.
    Ghosh S, Watanabe RM, Hauser ER, et al. Type 2 diabetes: Evidence for linkage on chromosme 20 in Finnish affected sib pairs. Proc Natl Acad Sci USA 1999;96:2198–2203.PubMedCrossRefGoogle Scholar
  77. 77.
    Fowden AL. The role of insulin in fetal growth. Early Human Development 1992;29:177–181.PubMedCrossRefGoogle Scholar
  78. 78.
    Fowden AL. Insulin deficiency: effects on fetal growth and development. Journal of Paediatrics and Child Health 1993;29:6–11.PubMedCrossRefGoogle Scholar
  79. 79.
    Hill DE. Insulin and fetal growth. Diabetes and Other Endocrine Disorders During Pregnancy and in the Newborn. New York: Alan R Liss Inc., 1976:127–139.Google Scholar
  80. 80.
    Hill DJ, Milner RDG. Insulin as a growth factor. Pediatric Research 1985;19:879–886.PubMedCrossRefGoogle Scholar
  81. 81.
    Hales CN, Barker DJP, Clark PMS, et al. Fetal and infant growth and impaired glucose tolerance at age 64. BMJ 1991;303:1019–1022.PubMedCrossRefGoogle Scholar
  82. 82.
    Hattersley AT, Tooke JE. The fetal insulin hypothesis: an alternative explanation of the association of low birth weight with diabetes and vascular disease. Lancet 1999;353:1789–92.PubMedCrossRefGoogle Scholar
  83. 83.
    Inagaki N, Gonoi T, Clement JP, et al. Reconstitution of IKATP: an inward rectifier subunit plus the sulfonylurea receptor. Science 1995;270:1166–1170.PubMedCrossRefGoogle Scholar
  84. 84.
    Thomas PM, Cote GJ, Wohllk K, et al. Mutations in the sulfonylurea receptor gene in familial persistent hyperinsulinemic hypoglycemia of infancy. Science 1995;268:426–429.PubMedCrossRefGoogle Scholar
  85. 85.
    Thomas P, Ye Y, Lightner E. Mutation of the pancreatic islet inward rectifier Kir6.2 also leads to familial persistent hyperinsulinemic hypoglycemia of infancy. Hum Mol Genet 1996;5:1809–1812.PubMedCrossRefGoogle Scholar
  86. 86.
    Edlund H. Transcribing Pancreas. Diabetes 1998;47:1817–1823.PubMedCrossRefGoogle Scholar
  87. 87.
    Barker DJ. Intrauterine programming of adult disease. Molecular Medicine Today 1995;1:418–23.PubMedCrossRefGoogle Scholar
  88. 88.
    Hales CN. The pathogenesis of NIDDM. Diabetologia 1994;37:S162–8.PubMedCrossRefGoogle Scholar
  89. 89.
    Hales CN, Barker DJP. Type 2 (non-insulin dependent) diabetes mellitus - the thrifty phenotype hypothesis. Diabetologia 1992;35:595–601.PubMedCrossRefGoogle Scholar
  90. 90.
    Wright NM, Metzger DL, Borowitz SM, Clarke WL. Permanent neonatal diabetes mellitus and pancreatic exocrine insufficiency resulting from congenital pancreatic agenesis. Am J Dis Child 1993;147:607–609.PubMedGoogle Scholar
  91. 91.
    Temple 1K, James RS, Crolla JA, et al. An imprinted gene(s) for diabetes? Nat Genet 1995;9:110–112.PubMedCrossRefGoogle Scholar
  92. 92.
    Temple IK, Gardner RJ, Robinson DO, et al. Further evidence for an imprinted gene for neonatal diabetes localised to chromosome 6q22-q23. Hum Molec Genet 1996;5:1117–1124.PubMedCrossRefGoogle Scholar
  93. 93.
    Shield JPH. Neonatal diabetes. In: Shield JPH, Baum JD, eds. Childhood Diabetes. Vol. 4. London: Bailliere Tindall, 1996:681–740.Google Scholar
  94. 94.
    Aparicio L, Carpenter MW, Schwartz R, Gruppuso PA. Prenatal diagnosis of familial neonatal hyperinsulinemia. Acta Paediat 1993;82:683–686.PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2001

Authors and Affiliations

  • Julie C. Evans
    • 1
  • Timothy M. Frayling
    • 1
  • Andrew T. Hattersley
    • 1
  1. 1.Department of Vascular Medicine and Diabetes Research School of Postgraduate Medicine and Health Sciences Barrack RoadExeter, DevonUK

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