MODY due to hepatocyte nuclear factor 1-beta mutations

HNF1B mutations are an uncommon cause of MODY. Mutations in this gene cause "RCAD syndrome" (Renal Cysts And Diabetes) and are associated with a syndrome of developmental renal, pancreas and genito-urinary anomalies. This leads to a variable phenotype. Patients with HNF1B mutations are not sulphonylurea sensitive and usually require insulin treatment.


HNF1B mutations are an uncommon cause of MODY and represent ~5% of MODY cases in the UK[1]. At least one third of cases are due to deletions of the whole gene or one or more exons of HNF1B gene[2] and de novo mutations occur in 30-50% of cases. The phenotype associated with heterozygous HNF1B mutations is markedly different from HNF1A mutations[3]. This is somewhat surprising as these two transcription factors share >90% homology in their DNA binding domains and recognise the same target DNA binding site. They can function as homodimers or heterodimers [4]. The differences in phenotype reflect the different timing and sites of expression of these transcription factors. HNF1B has a critical role in early embryogenesis of several organs including pancreatic beta-cell maturation before differentiation into exocrine and endocrine cells[5]. Furthermore the predominant site of HNF1B expression is the kidney while the predominant site of HNF1A expression is the pancreas and liver.

Clinical Features

Patients with HNF1B-MODY rarely present with isolated diabetes [6]. Renal developmental disease is the core phenotype in these patients, most frequently renal cysts (hence also named as renal cysts and diabetes (RCAD) syndrome), as well as renal dysplasia, renal tract malformations (e.g. single kidney, horseshoe kidney) and impaired renal function including tubular transport abnormalities [7] [8]. The extra-renal phenotype of HNF1B mutations is highly variable and includes genital-tract malformations, abnormal liver function tests, gout and hyperuricaemia, pancreatic atrophy with both exocrine and endocrine dysfunction and biliary tract malformations. Birth weight of affected individuals is reduced by ~800g due to reduced insulin secretion in utero. Neonatal diabetes has also been reported [9]. Diabetes is due to insulin resistance and beta-cell dysfunction, and typically presents after the renal disease. Clinical manifestations of insulin resistance include hyperinsulinaemia, elevated triglycerides and reduced high density lipoprotein [3]. Physiological studies have suggested that suppression of endogenous glucose production by insulin is impaired in patients with HNF1B mutations whilst peripheral insulin sensitivity is preserved [10]). When diabetes occurs with HNF1B mutations, there is usually associated pancreatic atrophy and exocrine insuficiency. HNF1B-MODY should be suspected in children or young adults with diabetes with associated non-diabetic renal disease even in the absence of relevant family history.


In contrast to those with HNF1A-MODY, these patients are not sensitive to sulphonylureas. Patients with diabetes due to HNF1B mutations frequently require early treatment with insulin therapy.


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  2. ^ Bellanne-Chantelot, C., S. Clauin, D. Chauveau, P. Collin, M. Daumont, C. Douillard, D. Dubois-Laforgue, L. Dusselier, J.F. Gautier, M. Jadoul, M. Laloi-Michelin, L. Jacquesson, E. Larger, J. Louis, M. Nicolino, J.F. Subra, J.M. Wilhem, J. Young, G. Velho, and J. Timsit, 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, 2005. 54(11): p. 3126-32.

  3. ^ Pearson, E.R., M.K. Badman, C.R. Lockwood, P.M. Clark, S. Ellard, C. Bingham, and A.T. Hattersley, Contrasting diabetes phenotypes associated with hepatocyte nuclear factor-1alpha and -1beta mutations. Diabetes Care, 2004. 27(5): p. 1102-7.

  4. ^ Rey-Campos, J., T. Chouard, M. Yaniv, and S. Cereghini, vHNF1 is a homeoprotein that activates transcription and forms heterodimers with HNF1. The EMBO Jurnal, 1991. 10(6): p. 1445-1457.

  5. ^ Maestro, M.A., S.F. Boj, R.F. Luco, C.E. Pierreux, J. Cabedo, J.M. Servitja, M.S. German, G.G. Rousseau, F.P. Lemaigre, and J. Ferrer, Hnf6 and Tcf2 (MODY5) are linked in a gene network operating in a precursor cell domain of the embryonic pancreas. Hum Mol Genet, 2003. 12(24): p. 3307-14.

  6. ^ Edghill, E.L., K. Stals, R.A. Oram, M.H. Shepherd, A.T. Hattersley, and S. Ellard, HNF1B deletions in patients with young-onset diabetes but no known renal disease. Diabet Med, 2013. 30(1): p. 114-7.

  7. ^ Bingham, C. and A.T. Hattersley, Renal cysts and diabetes syndrome resulting from mutations in hepatocyte nuclear factor-1beta. Nephrol Dial Transplant, 2004. 19(11): p. 2703-8.

  8. ^ Bellanne-Chantelot C, Chauveau D, Gautier JF, Dubois-Laforgue D, Clauin S, Beaufils S, Wilhelm JM, Boitard C, Noel LH, Velho G, Timsit J Clinical spectrum associated with hepatocyte nuclear factor-1beta mutations. Annals of internal medicine. 2004 140:510-517

  9. ^ Edghill, E.L., C. Bingham, A.S. Slingerland, J.A. Minton, C. Noordam, S. Ellard, and A.T. Hattersley, Hepatocyte nuclear factor-1 beta mutations cause neonatal diabetes and intrauterine growth retardation: support for a critical role of HNF-1beta in human pancreatic development. Diabet Med, 2006. 23(12): p. 1301-6.

  10. ^ Brackenridge, A., E.R. Pearson, F. Shojaee-Moradie, A.T. Hattersley, D. Russell-Jones, and A.M. Umpleby, Contrasting insulin sensitivity of endogenous glucose production rate in subjects with hepatocyte nuclear factor-1beta and -1alpha mutations. Diabetes, 2006. 55(2): p. 405-11.


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