Mutations in transcription factor as rare causes of diabetes in pregnancy

MODY1 and MODY3 represent rare causes of diabetes in pregnancy. Establishing a molecular diagnosis of MODY1 or MODY3 during pregnancy may be important for minimizing risk of perinatal complications and for improving glycemic control after pregnancy. The objective of the study was to evaluate the contribution of mutations in HNF4A and HNF1A genes in development of diabetes in pregnancy and to describe clinical characteristics of diabetes in pregnancy associated with these mutations. 230 pregnant women (20-43 years) with different type of glucose intolerance complicated during their current pregnancy were included in the study. A custom NGS panel targeting 28 diabetes causative genes was used for sequencing. Heterozygous mutations in HNF4A and HNF1A genes were detected in 3% of cases. Mutations p.I271T in HNF4A gene and p.L148F, p.Y265C, p.G288W in HNF1A gene were novel. This study includes a description of patients with pregnancy diabetes due to mutations in hepatocyte nuclear factors.

1. Kleinberger JW, Maloney KA, Pollin TI. The Genetic Architecture of Diabetes in Pregnancy: Implications for Clinical Practice. Am J Perinatol. 2016;33(13):1319-1326. doi: https://doi.org/10.1055/s-0036-1592078

2. Kleinberger JW, Pollin TI. Undiagnosed MODY: Time for Action. Curr Diab Rep. 2015;15(12):110. doi: https://doi.org/10.1007/s11892-015-0681-7

3. Velho G, Hattersley AT, Froguel P. Maternal diabetes alters birth weight in glucokinase-deficient (MODY2) kindred but has no influence on adult weight, height, insulin secretion or insulin sensitivity. Diabetologia. 2000;43(8):1060-1063. doi: https://doi.org/10.1007/s001250051490

4. Doddabelavangala Mruthyunjaya M, Chapla A, Hesarghatta Shyamasunder A, et al. Comprehensive Maturity Onset Diabetes of the Young (MODY) Gene Screening in Pregnant Women with Diabetes in India. PLoS One. 2017;12(1):e0168656. doi: https://doi.org/10.1371/journal.pone.0168656

5. Zurawek M, Wender-Ozegowska E, Januszkiewicz-Lewandowska D, et al. GCK and HNF1alpha mutations and polymorphisms in Polish women with gestational diabetes. Diabetes Res Clin Pract. 2007;76(1):157-158. doi: https://doi.org/10.1016/j.diabres.2006.08.001

6. Weng J, Ekelund M, Lehto M, et al. Screening for MODY mutations, GAD antibodies, and type 1 diabetes--associated HLA genotypes in women with gestational diabetes mellitus. Diabetes Care. 2002;25(1):68-71. doi: https://doi.org/10.2337/diacare.25.1.68

7. Gjesing AP, Rui G, Lauenborg J, et al. High Prevalence of Diabetes-Predisposing Variants in MODY Genes Among Danish Women With Gestational Diabetes Mellitus. J Endocr Soc. 2017;1(6):681-690. doi: https://doi.org/10.1210/js.2017-00040

8. Richards S, Aziz N, Bale S, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015;17(5):405-424. doi: https://doi.org/10.1038/gim.2015.30

9. Lek M, Karczewski KJ, Minikel EV, et al. Analysis of protein-coding genetic variation in 60,706 humans. Nature. 2016;536(7616):285-291. doi: https://doi.org/10.1038/nature19057

10. den Dunnen JT, Dalgleish R, Maglott DR, et al. HGVS Recommendations for the Description of Sequence Variants: 2016 Update. Hum Mutat. 2016;37(6):564-569. doi: https://doi.org/10.1002/humu.22981

11. Yamagata K, Furuta H, Oda N, et al. Mutations in the hepatocyte nuclear factor-4alpha gene in maturity-onset diabetes of the young (MODY1). Nature. 1996;384(6608):458-460. doi: https://doi.org/10.1038/384458a0

12. Yamagata K, Oda N, Kaisaki PJ, et al. Mutations in the hepatocyte nuclear factor-1alpha gene in maturity-onset diabetes of the young (MODY3). Nature. 1996;384(6608):455-458. doi: https://doi.org/10.1038/384455a0

13. Ellard S, Colclough K. Mutations in the genes encoding the transcription factors hepatocyte nuclear factor 1 alpha (HNF1A) and 4 alpha (HNF4A) in maturity-onset diabetes of the young. Hum Mutat. 2006;27(9):854-869. doi: https://doi.org/10.1002/humu.20357

14. Shih DQ, Stoffel M. Dissecting the transcriptional network of pancreatic islets during development and differentiation. Proc Natl Acad Sci U S A. 2001;98(25):14189-14191. doi: https://doi.org/10.1073/pnas.251558998

15. Odom DT, Zizlsperger N, Gordon DB, et al. Control of pancreas and liver gene expression by HNF transcription factors. Science. 2004;303(5662):1378-1381. doi: https://doi.org/10.1126/science.1089769

16. Ellard S. Hepatocyte nuclear factor 1 alpha (HNF-1?) mutations in maturity-onset diabetes of the young. Hum Mutat. 2000;16(5):377-385. doi: https://doi.org/10.1002/1098-1004(200011)16:5<377::aid-humu1>3.0.co;2-2

17. Galan M, Garcia-Herrero CM, Azriel S, et al. Differential effects of HNF-1alpha mutations associated with familial young-onset diabetes on target gene regulation. Mol Med. 2011;17(3-4):256-265. doi: https://doi.org/10.2119/molmed.2010.00097

18. Bjorkhaug L, Sagen JV, Thorsby P, et al. Hepatocyte nuclear factor-1 alpha gene mutations and diabetes in Norway. J Clin Endocrinol Metab. 2003;88(2):920-931. doi: https://doi.org/10.1210/jc.2002-020945

19. Tonooka N, Tomura H, Takahashi Y, et al. High frequency of mutations in the HNF-1alpha gene in non-obese patients with diabetes of youth in Japanese and identification of a case of digenic inheritance. Diabetologia. 2002;45(12):1709-1712. doi: https://doi.org/10.1007/s00125-002-0978-3

20. Hattersley AT. Maturity-onset diabetes of the young: clinical heterogeneity explained by genetic heterogeneity. Diabet Med. 1998;15(1):15-24. doi: https://doi.org/10.1002/(sici)1096-9136(199801)15:1<15::aid-dia562>3.0.co;2-m

21. Toaima D, Nake A, Wendenburg J, et al. Identification of novel GCK and HNF1A/TCF1 mutations and polymorphisms in German families with maturity-onset diabetes of the young (MODY). Hum Mutat. 2005;25(5):503-504. doi: https://doi.org/10.1002/humu.9334

22. Fajans SS, Bell GI, Polonsky KS. Molecular mechanisms and clinical pathophysiology of maturity-onset diabetes of the young. N Engl J Med. 2001;345(13):971-980. doi: https://doi.org/10.1056/NEJMra002168

23. Stride A, Ellard S, Clark P, et al. Beta-cell dysfunction, insulin sensitivity, and glycosuria precede diabetes in hepatocyte nuclear factor-1alpha mutation carriers. Diabetes Care. 2005;28(7):1751-1756. doi: https://doi.org/10.2337/diacare.28.7.1751

24. Pearson ER, Boj SF, Steele AM, et al. Macrosomia and hyperinsulinaemic hypoglycaemia in patients with heterozygous mutations in the HNF4A gene. PLoS Med. 2007;4(4):e118. doi: https://doi.org/10.1371/journal.pmed.0040118

25. Shepherd M, Brook AJ, Chakera AJ, Hattersley AT. Management of sulfonylurea-treated monogenic diabetes in pregnancy: implications of placental glibenclamide transfer. Diabet Med. 2017;34(10):1332-1339. doi: https://doi.org/10.1111/dme.13388