Liver, kidneys and diabetes: three faces of HNF1B gene deficit

Česká verzia

Authors: Jan Lebl; Stanislava Koloušková; Petra Dušátková; Ondřej Cinek; Lenka Dušátková; Tomáš Dědič; Radana Kotalová; Zdeněk Šumník; Tomáš Seeman; Štěpánka Průhová
Authors place of work: Pediatrická klinika 2. LF UK a FN Motol Praha, přednosta prof. MUDr. Jan Lebl, CSc.
Published in the journal: Vnitř Lék 2014; 60(9): 725-729
Category:

Summary

The renal cysts and diabetes syndrome (RCAD), also known as HNF1B-MODYor MODY5, is caused by the deletion or point mutation of HNF1B gene which leads to the depletion of HNF1B transcription factor. The main clinical components of RCAD include cystic kidney disease or other developmental anomalies of the kidneys and diabetes mellitus which typically manifests in the second decade of life or later. Renal disorders may lead to the development of chronic renal insufficiency already in childhood or young adulthood. The other symptoms include hepatic impairment - cholestatic jaundice in middle-aged patients, sometimes even neonatal cholestasis, atrophy of the pancreas with the impairment of exocrine pancreatic secretion and some congenital anomalies of the genital tract. As opposed to the other forms of MODY diabetes, the family history may not be positive because most of the deviations of HNF1B appear de novo. We associate RCAD in particular with adults suffering from diabetes and cystic kidney disease and/or cholestatic jaundice and children with cystic kidney disease of unclear etiology, even without the presence of diabetes. A supportive finding may be hypomagnesemia which occurs in up to 70 % of patients diagnosed with HNF1B related disease and hyperuricemia.

Key words:
HNF1B – MODY – RCAD – diabetes mellitus – cholestatic jaundice

Zdroje

1. Limaye PB, Alarcón G, Walls AL et al. Expression of specific hepatocyte and cholangiocyte transcription factors in human liver disease and embryonic development. Lab Invest 2008; 88(8): 865–872.

2. Raynaud P, Carpentier R, Antoniou A et al. Biliary differentiation and bile duct morphogenesis in development and disease. Int J Biochem Cell Biol 2011; 43(2): 245–256.

3. Strazzabosco M, Fabris L. Development of the bile ducts: Essentials for the clinical hepatologist. J Hepatol 2012; 56(5): 1159–1170.

4. Pruhova S, Ek J, Lebl J et al. Genetic epidemiology of MODY in the Czech Republic: Novel mutations in the MODY genes HNF-4a, GCK and HNF-1a. Diabetologia 2003; 46(2): 291–295.

5. Hansen SK, Parrizas M, Jensen ML et al. Genetic evidence that HNF-1alpha-dependent transcriptional control of HNF-4alpha is essential for human pancreatic beta cell function. J Clin Invest 2002; 110(6): 827–833.

6. Pearson ER, Pruhova S, Tack CJ et al. Molecular genetics and phenotypic characteristics of MODY caused by hepatocyte nuclear factor 4alpha mutations in a large European collection. Diabetologia 2005; 48(5): 878–885.

7. Horikawa Y, Iwasaki N, Hara M et al. Mutation in hepatocyte nuclear factor-1 beta gene (TCF2) associated with MODY. Nat Genet 1997; 17(4): 384–385.

8. Nishigori H, Yamada S, Kohama T et al. Frameshift mutation, A263fsinsGG, in the hepatocyte nuclear factor-1beta gene associated with diabetes and renal dysfunction. Diabetes 1998; 47(8): 1354–1355.

9. Beards F, Frayling T, Bulman M et al. Mutations in hepatocyte nuclear factor 1beta are not a common cause of maturity-onset diabetes of the young in the U.K. Diabetes 1998; 47(7): 1152–1154.

10. Lindner TH, Njolstad PR, Horikawa Y et al. 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 1999; 8(11): 2001–2008.

11. Kolatsi-Joannou M, Bingham C, Ellard S et al. Hepatocyte nuclear factor-1beta: a new kindred with renal cysts and diabetes and gene expression in normal human development. J Am Soc Nephrol 2001; 12(10): 2175–2180.

12. Montoli A, Colussi G, Massa O et al. 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 2002; 40(2): 397–402.

13. Bingham C, Hattersley AT Renal cysts and diabetes syndrome resulting from mutations in hepatocyte nuclear factor-1beta. Nephrol Dial Transplant 2004; 19(11): 2703–2708.

14. Roelandt P, Antoniou A, Libbrecht L et al. HNF1B deficiency causes ciliary defects in human cholangiocytes. Hepatology 2012; 56(3): 1178–1181.

15. Kitanaka S, Miki Y, Hayashi Y et al. 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 2004; 89(3): 1369–1378.

16. Beckers D, Bellanné-Chantelot C, Maes M. Neonatal cholestatic jaundice as the first symptom of a mutation in the hepatocyte nuclear factor-1beta gene (HNF-1beta). J Pediatr 2007; 150(3): 313–314.

17. Raile K, Klopocki E, Holder M et al. Expanded clinical spectrum in hepatocyte nuclear factor 1b-maturity-onset diabetes of the young. J Clin Endocrinol Metab 2009; 94(7): 2658–2664.

18. Gonc EN, Ozturk BB, Haldorsen IS et al. HNF1B mutation in a Turkish child with renal and exocrine pancreas insufficiency, diabetes and liver disease. Pediatr Diabetes 2012; 13(2): e1-e5.

19. Chen YZ, Gao Q, Zhao XZ et al. Systematic review of TCF2 anomalies in renal cysts and diabetes syndrome/maturity onset diabetes of the young type 5. Chin Med J (Engl) 2010; 123(22): 3326–3333.

20. Heidet L, Decramer S, Pawtowski A et al. Spectrum of HNF1B mutations in a large cohort of patients who harbor renal diseases. Clin J Am Soc Nephrol 2010; 5(6): 1079–1090.

21. Ulinski T, Lescure S, Beaufils S et al. Renal phenotypes related to hepatocyte nuclear factor-1beta (TCF2) mutations in a pediatric cohort. J Am Soc Nephrol 2006; 17(2): 497–503.

22. Weber S, Moriniere V, Knüppel T et al. Prevalence of mutations in renal developmental genes in children with renal hypodysplasia: results of the ESCAPE study. J Am Soc Nephrol 2006; 17(10): 2864–2870.

23. Thomas R, Sanna-Cherchi S, Warady BA et al. HNF1B and PAX2 mutations are a common cause of renal hypodysplasia in the CKiD cohort. Pediatr Nephrol 2011; 26(6): 897–903.

24. Adalat S, Woolf AS, Johnstone KA et al. HNF1B mutations associate with hypomagnesemia and renal magnesium wasting. J Am Soc Nephrol 2009; 20(5): 1123–1131.

25. Faguer S, Decramer S, Chassaing N et al. Diagnosis, management, and prognosis of HNF1B nephropathy in adulthood. Kidney Int 2011; 80(7): 768–776.