Rare causes of MODY

Mutations in IPF1, NEUROD1, CEL, INS, ABCC8 and KCNJ11 are rare causes of MODY, and together account for <5% of all confirmed MODY cases. These rare monogenic causes of diabetes have provided interesting insights into biological pathways in the pancreas and pathogenesis of dysglycaemia.

Insulin promoter factor 1 (IPF1, also known as PDX1) is a transcription factor with a critical role in pancreatic development. Animal studies have shown that the pancreas is absent in Ipf1 knockout mice and diabetes develops if Ipf1 is disrupted after formation of the beta-cells [1][2] Therefore the IPF1 gene was an obvious candidate for monogenic diabetes. In the original family described, a homozygous IPF1 mutation was found in a child with pancreas agenesis who had been investigated for neonatal diabetes and severe exocrine pancreatic insufficiency. The parents of the child were second cousins and in other family members heterozygous IPF1 mutations co-segregated with young-onset diabetes [3]. Other evidence for IPF1 as a MODY gene is limited. Some rare variants were reported but were subsequently found to be present in similar frequencies in controls [4]. There have been a number of other reports of pancreatic agenesis and of neonatal diabetes without absense of the pancreas [5].

NEUROD1 is another transcription factor important in pancreatic development and as a regulator of insulin gene expression. In 1999 a NEUROD1 mutation which co-segregated with young-onset diabetes in one family meeting MODY criteria was described[6]. A further five MODY families with NEUROD1 mutations have been reported since then [7] [8] [9] although doubts remain about the pathogenicity of some of the variants. Obesity was frequently observed in these families, making the differentiation from type 2 diabetes difficult. Several large studies of families with MODY phenotypes have failed to identify NEUROD1 variants. More recently homozygous NEUROD1 mutations have been reported as a rare cause of permanent neonatal diabetes mellitus (PNDM) [10].

CEL encodes the lipolytic enzyme carboxyl-ester lipase which is responsible for the hydrolysis of cholesterol esters. A syndrome of young adult-onset diabetes and pancreatic exocrine dysfunction caused by mutations in a non-coding region of CEL was described in 2 Norwegian MODY pedigrees [11]. CEL is only expressed in the pancreatic acinar cell; therefore, beta-cell dysfunction was unexpected. Patients with CEL mutations frequently complain of symptoms suggestive of pancreatic exocrine deficiency such as steatorrhea and intermittent abdominal pain, In some clinical manifestations are mild, while others develop a demyelinating neuropathy of uncertain aetiology [12]. Although the genetic evidence for causation seems solid, no further families have been reported.

Mutations in INS, ABCC8 and KCNJ11 are also rare causes of a MODY presentation. Mutations in these genes more commonly cause either permanent or transient Neonatal diabetes. Mutations in these genes probably each cause about 1% of classic MODY cases, and in the case of ABCC8 and KCNJ11 mutation carriers may lead to treatment change to sulphonylureas. Therefore, they are increasingly being added to diagnostic testing panels.

Mutations in other genes, including BLK, KLF11 and PAX4, have also been reported as causal for MODY, but the genetic support for these is uncertain or lacking [13].


  1. ^ Jonsson, J., L. Carlsson, T. Edlund, and H. Edlund, Insulin-promoter-factor 1 is required for pancreas development in mice. Nature, 1994. 371(6498): p. 606-9.

  2. ^ Ahlgren, U., J. Jonsson, L. Jonsson, K. Simu, and H. Edlund, Beta-cell-specific inactivation of the mouse Ipf1/Pdx1 gene results in loss of the beta-cell phenotype and maturity onset diabetes. Genes Dev, 1998. 12(12): p. 1763-8.

  3. ^ Stoffers, D.A., J. Ferrer, W.L. Clarke, and J.F. Habener, Early-onset type-II diabetes mellitus (MODY4) linked to IPF1. Nature Genetics, 1997. 17: p. 138-139.

  4. ^ Edghill, E.L., A. Khamis, M.N. Weedon, M. Walker, G.A. Hitman, M.I. McCarthy, K.R. Owen, S. Ellard, T.H. A, and T.M. Frayling, Sequencing PDX1 (insulin promoter factor 1) in 1788 UK individuals found 5% had a low frequency coding variant, but these variants are not associated with Type 2 diabetes. Diabet Med, 2011. 28(6): p. 681-4.

  5. ^ De Franco, E., C. Shaw-Smith, S.E. Flanagan, E.L. Edghill, J. Wolf, V. Otte, F. Ebinger, P. Varthakavi, T. Vasanthi, S. Edvardsson, A.T. Hattersley, and S. Ellard, Biallelic PDX1 (insulin promoter factor 1) mutations causing neonatal diabetes without exocrine pancreatic insufficiency. Diabet Med, 2013. 30(5): p. e197-200.

  6. ^ Malecki, M.T., U.S. Jhala, A. Antonellis, L. Fields, A. Doria, T. Orban, M. Saad, J.H. Warram, M. Montminy, and A.S. Krolewski, Mutations in NEUROD1 are associated with the development of Type 2 diabetes mellitus. Nature Genetics, 1999. 23(3): p. 323-328.

  7. ^ Kristinsson, S.Y., E.T. Thorolfsdottir, B. Talseth, E. Steingrimsson, A.V. Thorsson, T. Helgason, A.B. Hreidarsson, and R. Arngrimsson, MODY in Iceland is associated with mutations in HNF-1alpha and a novel mutation in NeuroD1. Diabetologia, 2001. 44(11): p. 2098-103.

  8. ^ Liu, L., H. Furuta, A. Minami, T. Zheng, W. Jia, K. Nanjo, and K. Xiang, A novel mutation, Ser159Pro in the NeuroD1/BETA2 gene contributes to the development of diabetes in a Chinese potential MODY family. Mol Cell Biochem, 2007. 303(1-2): p. 115-20.

  9. ^ Gonsorcikova, L., S. Pruhova, O. Cinek, J. Ek, T. Pelikanova, T. Jorgensen, H. Eiberg, O. Pedersen, T. Hansen, and J. Lebl, Autosomal inheritance of diabetes in two families characterized by obesity and a novel H241Q mutation in NEUROD1. Pediatr Diabetes, 2008. 9(4 Pt 2): p. 367-72.

  10. ^ Rubio-Cabezas, O., J.A. Minton, I. Kantor, D. Williams, S. Ellard, and A.T. Hattersley, Homozygous mutations in NEUROD1 are responsible for a novel syndrome of permanent neonatal diabetes and neurological abnormalities. Diabetes, 2010. 59(9): p. 2326-31.

  11. ^ Raeder, H., S. Johansson, P.I. Holm, I.S. Haldorsen, E. Mas, V. Sbarra, I. Nermoen, S.A. Eide, L. Grevle, L. Bjorkhaug, J.V. Sagen, L. Aksnes, O. Sovik, D. Lombardo, A. Molven, and P.R. Njolstad, Mutations in the CEL VNTR cause a syndrome of diabetes and pancreatic exocrine dysfunction. Nat Genet, 2006. 38(1): p. 54-62.

  12. ^ Vesterhus, M., H. Raeder, H. Aurlien, C.G. Gjesdal, C. Bredrup, P.I. Holm, A. Molven, L. Bindoff, A. Berstad, and P.R. Njolstad, Neurological features and enzyme therapy in patients with endocrine and exocrine pancreas dysfunction due to CEL mutations. Diabetes Care, 2008. 31(9): p. 1738-40.

  13. ^ Bonnefond, A., L. Yengo, J. Philippe, A. Dechaume, I. Ezzidi, E. Vaillant, A.P. Gjesing, E.A. Andersson, S. Czernichow, S. Hercberg, S. Hadjadj, G. Charpentier, O. Lantieri, B. Balkau, M. Marre, O. Pedersen, T. Hansen, P. Froguel, and M. Vaxillaire, Reassessment of the putative role of BLK-p.A71T loss-of-function mutation in MODY and type 2 diabetes. Diabetologia, 2013. 56(3): p. 492-6.


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