Pediatrická klinika a Ústav lékařské mikrobiologie
Univerzita Karlova, 2. lékařská fakulta a
Fakultní nemocnice v Motole

Home
Projekty
MODY diabetes
MODY6

MODY6

Štěpánka Průhová

MODY 6 je vyvolán mutací genu pro protein neurogenní diferenciace NeuroD1, někdy nazývaný BETA2 (b-cell E-box transactivator 2). NeuroD1 je tzv. helix-loop-helix (HLH) protein patřící do transkripční regulační sítě b-buněk.(18)

Klinický obraz

Dosud byly popsány mutace u dvou rodin s diabetem. V prvním případě se jednalo o obézní  pacienty s vysokou koncentrací inzulinu, s typickým fenotypem diabetu 2. typu. U druhé rodiny průběh diabetu připomínal spíše MODY 3. U obou rodin, u nichž byla nalezena mutace v genu pro NeuroD1, byl zjištěn značný familiární výskyt diabetu. U žádného z nositelů mutace nedošlo ke vzniku onemocnění CNS nebo gastrointestinálního traktu – tkání, v nichž je gen pro NeuroD1 také exprimován.(18)

Komplikace

Četnost komplikací diabetu není u MODY 6 známa.

Patofyziologie

NeuroD1 patří mezi faktory diferenciace pankreatu, uplatňuje se ale také v neurogenezi (odtud název protein neurogenní diferenciace). NeuroD1 byl dokonce v nervové tkáni objeven jako první, později byla prokázána jeho důležitost při vývoji pankreatu a při metabolismu b-buněk. Protein se exprimuje v pankreatických endokrinních buňkách, tenkém střevě a mozku. NeuroD1 se váže na kritický E-box motiv na promotoru inzulinového genu. Zdá se, že dokáže přímo ovlivňovat tvorbu inzulinu. Je součástí transkripční regulační sítě b-buněk a je ovlivňován některými dalšími faktory, jako např. HNF-1a (viz obr. 2). Myš s cíleně poškozeným genem pro NeuroD1 umírá s projevy diabetu brzy po narození. Má významně redukovanou masu ostrůvkových buněk v pankreatu, zejména je snížené množství b-buněk.(19) Ostrůvky mají abnormální morfologii, je porušena jejich organizace do tzv. klastrů. Skutečná role NeuroD1 v regulaci fungování endokrinního pankreatu se teprve hledá.

Genetika

V roce 2001 byl gen pro NeuroD1 označen za MODY 6 gen.(7) NeuroD1 je lokalizován na chromosomu 2q a obsahuje dva exony, z nichž exon 1 se při syntéze proteinu nepřepisuje. Nalezené mutace vedou ke vzniku diabetu nejspíše tím, že narušují vazbu NeuroD1 na INS promotor inzulinového genu, nebo tím, že porušují funkci aktivační domény faktoru.

Použitá literatura:

  1. BEARDS, F., FRAYLING, T., BULMAN, M., et al. Mutations in hepatocyte nuclear factor 1b are not a common cause of maturity-onset diabetes of the young in the U.K. Diabetes, 1998, 47, p. 1152–1154.
  2. BOILEAU, P., WOLFRUM, CH., SHIH, D., et al. Decreased glibenclamide uptake in hepatocytes of hepatocyte nuclear factor-1a deficient mice. Diabetes, 2002, 51, p. S343–S348.
  3. BINGHAM, C., ELLARD, S., ALLEN, L., et al. Abnormal nephron development associated with a frameshift mutation in the transcription factor hepatocyte nuclear factor-1b. Kidney Int, 2000, 57, p. 898–907.
  4. BINGHAM, C., ELLARD, S., COLE, T., et al. Solitary functioning kidney and diverse genital tract malformations associated with hepatocyte nuclear factor-1b  mutations. Kidney Int, 2002, 61, p. 1243–1251.
  5. CLOCQUET, AR., EGAN, JM., STOFFERS, DA. Impaired insulin secretion and increased insulin sensitivity in familial maturity-onset diabetes of the young 4 (insulin promoter factor 1 gene). Diabetes, 2000, 49, 1856–1864.
  6. ELLARD, S., BEARDS, F., ALLEN, LI., et al. A high prevalence of glucokinase mutations in gestational diabetic subjects selected by clinical criteria. Diabetologia, 2000, 43, p. 250–253.
  7. FAJANS, SS., BELL, GI., POLONSKY, KS. Molecular mechanisms and clinical pathophysiology of Maturity-Onset Diabetes of the Young. N Engl J Med, 2001, 345, p. 971–980.
  8. FRAYLING, T., EVANS, J., BULMAN, M., et al. Beta-cell genes and diabetes. Diabetes, 2001, 50, p. S94–S100.
  9. GLOYN, AL. Glucokinase (GCK) mutations in hyper- and hypoglycemia: maturity-onset diabetes of the young, permanent neonatal diabetes, and hyperinsulinemia in infancy. Human Mutat, 2003, 22, p. 353–362.
  10. HARA, M., LINDNER, T., PAZ, V., et al. Mutations in the coding region of the insulin promotor factor 1 gene are not a common cause of maturity-onset diabetes of the young in Japanese subjects. Diabetes, 1998, 47, p. 845–846.
  11. HANI, HE., SUAUD, L., BOUTIN, P., et al. A missense mutation in hepatocyte nuclear factor-4a , resulting in reduced transactivation activity, in human late-onset non-insulin- dependent diabetes mellitus. J Clin Invest, 1998, 101, p. 521–526.
  12. HANSEN, SK., PARRIZAS, M., JENSEN, ML., et al. Genetic evidence that HNF-1 alpha dependent transcriptional control of HNF-4 alpha is essential for human pancreatic b-cell function. J Clin Invest, 2002, 110, p. 827–833.
  13. HATTERSLEY, AT. Maturity-onset diabetes of the young: clinical heterogeneity explained by genetic heterogeneity. Diabet Med, 1998, 15, p. 15–24.
  14. HATTERSLEY, AT., BEARDS, F., BALLANTYNE, E., et al. Mutations in the glucokinase gene of the fetus result in reduced birth weight. Nat Genet, 1998, 19, p. 268–270.
  15. ISOMAA, B., HENRICSSON, M., LEHTO, M., et al. Chronic diabetic complications in patients with MODY 3 diabetes. Diabetologia, 1998, 41, p. 467–473.
  16. LEHTO, M., BITZEN, PO., ISOMAA, B., et al. Mutation in the HNF-4alpha gene affects insulin secretion and triglyceride metabolism. Diabetes, 1999, 48, p. 423–425.
  17. LEHTO, M., TUOMI, T., MAHTANI, M., et al. Characterization of the MODY 3 phenotype. J Clin Invest, 1997, 99, p. 582–591.
  18. MALECKI, MT., JHALA, US., ANTONELLIS, A., et al. Mutations in NeuroD1 are associated with the development of type 2 diabetes mellitus. Nature Genetics, 1999, 23, p. 323–328.
  19. NAYA, FJ., HUANG, HP., QIU, Y., et al. Diabetes, defective pancreatic morphogenesis, and abnormal enteroendocrine differentiation in BETA2/neuroD-deficient mice. Genes Dev, 1997, 11, p. 2323–2334.
  20. NISHIGORI, H., YAMADA, S., KOHAMA, T. et al. Frameshift mutation, A263fsinsGG, in the hepatocyte nuclear factor-1b gene associated with diabetes and renal dysfunction. Diabetes, 1998, 47, p. 1354–1355.
  21. NJOLSTAD, PR., SOVIK, O., CUESTA-MUNOZ, A., et al. Neonatal diabetes mellitus due to complete glucokinase deficiency. N Engl J Med, 2001, 344, p. 1588–1592.
  22. PEARSON, E., BADMAN, M., LOCKWOOD, C., et al. Contrasting diabetes phenotypes associated with hepatocyte nuclear factor-1a and –1b mutations. Diabetes Care, 2004, 27, p. 1102–1107.
  23. PEARSON, E., PRUHOVA, S., TACK, C., et al. Molecular genetics and phenotypic characteristics of MODY caused by hepatocyte nuclear factor 4 alfa mutations in a large European collection. Diabetologia, 2005, 48, p. 878–885.
  24. PEARSON, E., STARKEY, B., POWELL, R., et al. Genetic cause of hyperglycaemia and response to treatment in diabetes. Lancet, 2003, 362, p. 1275–1281.
  25. PEARSON, E., VELHO, G., CLARK, P., et al. Beta-cell genes and diabetes: quantitative and qualitative differences in the pathophysiology of hepatic nuclear factor-1a and glucokinase mutations. Diabetes, 2001, 50, p. S101–S107.
  26. PONTOGLIO, M., SREENAN, S., ROE, M., et al. Defective insulin secretion in hepatocyte nuclear factor 1a-deficient mice. J Clin Invest, 1998, 101, p. 2215–2222.
  27. PRŮHOVÁ, Š., EK, J., LEBL, J., et al. Genetic epidemiology of MODY in the Czech republic: new mutations in the MODY genes HNF-4a, GCK and HNF-1a. Diabetologia, 2003, 46, p. 291–295.
  28. RAEDER, H., JOHANSSON, S., HOLM, PI., et al. Mutations in the CEL VNTR cause a syndrome of diabetes and pancreatic exocrine dysfunction. Nat Genet, 2005, 20.
  29. SAGEN, J., BOSTAD, L., NJOLSTAD, P., et al. Enlarged nephrons and severe nondiabetic nephropathy in hepatocyte nuclear factor -1a (HNF-1a) mutation carriers. Kidney Int, 2003, 64, p. 793–800.
  30. SHIH, D., DANSKY, H., FLEISHER, M., et al. Genotype/phenotype relationships in HNF-4a/ MODY 1. Diabetes, 2002, 49, p. 832–837.
  31. SHIH, D., SCREENAN, S., MUNOZ, K., et al. Loss of HNF-1a function in mice leads to abnormal expression of genes involved in pancreatic islet development and metabolism. Diabetes, 2001, 50, p. 2472–2480.
  32. SO, WY., NG, MC., HORIKAWA, Y., et al. Genetic variants of hepatocyte nuclear factor- 1b  in Chinese young-onset diabetic patiens with nephropathy. J Diabetes Comp, 2003, 17, p. 369–373.
  33. SPYER, G., HATTERSLEY, AT., SYKES, JE., et al. Influence of maternal and fetal glucokinase mutations in gestational diabetes. Am J Obstet Gynecol, 2001, 185, p. 240–241.
  34. STOFFERS, DA., ZINKIN, NT., STANOJEVIC, V., et al. Pancreatic agenesis attributable to a single nukleotide deletion in the human IPF1 gene coding sequence. Nat Genet, 1997, 15, p. 106–110.
  35. STRIDE, A., VAXILLAIRE, M., TUOMI, T., et al. The genetic abnormality in the b cell determines the response to an oral glucose load. Diabetologia, 2002, 45, p. 427–435.
  36. SUAUD, L., HEMIMOU, Y., FORMSTECHER, P., et al. Functional study of the E276Q mutant hepatocyte nuclear factor-4 a found in type 1 maturity-onset diabetes of the young. Diabetes, 1999, 48, p. 1162–1167.
  37. TAPPY, L., DUSSOIX, P., IYNEDJIAN, P., et al. Abnormal regulation of glucose output in maturity onset diabetes of the young caused by a specific mutation of the glucokinase gene. Diabetes, 1997, 46, p. 204–208.
  38. TATTERSALL, R. Maturity-onset diabetes of the young: a clinical history. Diabet Med, 1998, 15, p. 11–14.
  39. VELHO, G., BLANCHÉ, 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, p. 217–224.
  40. VELHO, G., HATTERSLEY, AT., FROGUEL, P. Maternal diabetes alters birth weight in glucokinase-deficient (MODY 2) kindreds but has no influence on adult weight, height, insulin secretion or insulin sensitivity. Diabetologia, 2000, 43, p. 1060–1063.
  41. WANG, H., HAGENFELDT-JOHANSSON, K., OTTEN, L., et al. Experimental models of transcription factor – associated maturity-onset diabetes of the young. Diabetes, 2002, 51, p. S333–S342.
  42. YAMADA, S., TOMURA, H., NISHIGORI, H., et al. Identification of mutations in the hepatocyte nuclear factor-1a gene in Japanese subjects with early-onset NIDDM and functional analysis of the mutant proteins. Diabetes, 1999, 48, p. 645–648.
  43. YAMAGATA, K., YANG, Q., YAMAMOTO, K., et al. Mutation P291fsinsC in the transcription factor hepatocyte nuclear factor-1 a is dominant negative. Diabetes, 1998, 47, p. 1231–1235.

Nové Publikace