Current Science

Open Access Open Access  Restricted Access Subscription Access

Genetic Basis of Monogenic Diabetes


Affiliations
1 Department of Molecular Genetics, Madras Diabetes Research Foundation, #20, Golden Jubilee Biotech Park for Women Society, SIPCOT, Siruseri, Chennai 603 103, India
 

Advances in the understanding of monogenic causes of diabetes and the discovery of single-gene mutations responsible for different phenotypes have greatly increased our knowledge of β-cell physiology. Such advances have had implications for the individual patient diagnosed with the specific monogenic cause of diabetes, especially in maturity onset diabetes of the young (MODY) and neonatal diabetes mellitus (NDM). Genetic diagnosis of MODY is also likely to have important prognostic and therapeutic implications in majority of the patients with confirmed HNF1A and HNF4A mutations. Genetic screening and analyses have helped several neonatal infants carrying mutations in the KCNJ11 and ABCC8 genes to shift from insulin treatment to oral sulphonylurea drugs. The progress in genomics of monogenic diabetic forms has helped in translating the discoveries from bench to bedside in clinical care. Therefore, there is an urgent need to incorporate genetic testing for the genes implicated in monogenic diabetes like MODY and NDM in the diabetes clinics. Discoveries in genetic research methodology and understanding of genetic etiology will have great translational implications for disease treatment and follow-up.

Keywords

Genetic Screening, Maturity Onset Diabetes of the Young, Monogenic Diabetes, Neonatal Diabetes, Precision Medicine.
User
Notifications
Font Size

  • Flannick, J., Johansson, S. and Njølstad, P. R., Common and rare forms of diabetes mellitus: towards a continuum of diabetes subtypes. Nature Rev. Endocrinol., 2016, doi:10.1038.

  • Shields, B. M. et al., Maturity-onset diabetes of the young (MODY): how many cases are we missing? Diabetologia, 2010, 53, 2504–2508.

  • Irgens, H. U. et al., Prevalence of monogenic diabetes in the populationbased Norwegian Childhood Diabetes Registry. Diabetologia, 2013, 56, 1512–1519.

  • Pihoker, C. et al., Prevalence, characteristics and clinical diagnosis of maturity onset diabetes of the young due to mutations in HNF1A, HNF4A, and glucokinase: results from the SEARCH for Diabetes in Youth. J. Clin. Endocrinol. Metab., 2013, 98, 4055–4062.

  • Mohan, V., Alberti KGMM: diabetes in the tropics. In International Text Book of Diabetes Mellitus (eds Zimmet, P. et al.), John Wiley, Chichester, UK, 1997, 2nd edn, pp. 171–187.

  • Mohan, V. et al., High prevalence of maturity onset diabetes of the young (MODY). Diabetes Care, 1985, 8, 371–374.

  • Mohan, V. et al., C-peptide responses to glucose load in maturity-onset diabetes of the young (MODY). Diabetes Care, 1985, 8(1), 69–72.

  • Mohan, V. and Hitman, G. A., Studies in maturity-onset diabetes of the young (MODY) from South India. In The Proceedings of the Third Asian Symposium on Childhood and Juvenile Diabetes Mellitues, Thailand, 1992, vol. 56, pp. 55–58.

  • Froguel, P. et al., Close linkage of glucokinase locus on chromosome 7p to early-onset non-insulin-dependent diabetes mellitus. Nature, 1992, 356(6365), 162–164.

  • Fajans, S. S. and Bell, G. I., MODY: history, genetics, pathophysiology, and clinical decision making. Diabetes Care, 2011, 34, 1878–1884.

  • Gardner, D. S. and Tai, E. S., Clinical features and treatment of maturity onset diabetes of the young (MODY). Diabetes Metab. Syndr. Obes., 2012, 5, 101–108.

  • Feigerlova, E. et al., Aetiological heterogeneity of asymptomatic hyperglycaemia in children and adolescents. Eur. J. Pediatr., 2006, 165, 446–452.

  • Steele, A. M. et al., Prevalence of vascular complications among patients with glucokinase mutations and prolonged, mild hyperglycaemia. JAMA, 2014, 311, 279–286.

  • Steele, A. M. et al., Use of HbA1c in the identification of patients with hyperglycaemia caused by a glucokinase mutation: observational case control studies. PLoS ONE, 2013, 8(6), e65326; doi:10.1371.

  • Stride, A. et al., Cross-sectional and longitudinal studies suggest pharmacological treatment used in patients with glucokinase mutations does not alter glycaemia. Diabetologia, 2014, 57(1), 54–56.

  • Osbak, K. K. et al., Update on mutations in glucokinase (GCK) which cause maturity onset diabetes of the young, permanent neonatal diabetes, and hyperinsulinemic hypoglycemia. Hum. Mutat., 2009, 30(11), 1512–1526.

  • Glaser, B. et al., Familial hyperinsulinism caused by an activating glucokinase mutation. N. Engl. J. Med., 1998, 338(4), 226–230.

  • Spyer, G. et al., Pregnancy outcome in patients with raised blood glucose due to a heterozygous glucokinase gene mutation. Diabet Med., 2009, 26, 14–18.

  • Hattersley, A. T. et al., Mutations in the glucokinase gene of the etus result in reduced birth weight. Nat. Genet., 1998, 19, 268–270.

  • Ferrer, J., A genetic switch in pancreatic beta-cells: implications for differentiation and haploinsufficiency. Diabetes, 2002, 51, 2355–2362.

  • Owen, K. and Hattersley, A. T., Maturity-onset diabetes of the young: from clinical description to molecular genetic characterization. Best Pract. Res. Clin. Endocrinol. Metab., 2001, 15(3), 309–323.

  • Pearson, E. R. et al., Molecular genetics and phenotypic characteristics of MODY caused by hepatocyte nuclear factor 4 alpha mutations in a large European collection. Diabetologia, 2005, 48(5), 878–885.

  • McDonald, T. J. and Ellard, S., Maturity onset diabetes of the young: identification and diagnosis. Ann. Clin. Biochem., 2013 50(5), 403–415.

  • Colclough, K. et al., Mutations in the genes encoding the transcription factors hepatocyte nuclear factor 1 alpha and 4 alpha in maturity onset diabetes of the young and hyperinsulinemic hypoglycemia. Hum. Mutat., 2013, 34, 669–685.

  • Bellanné-Chantelot, C. et al., The type and the position of HNF1A mutation modulate age at diagnosis of diabetes in patients with maturity-onset diabetes of the young (MODY)-3. Diabetes, 2008, 57, 503–508.

  • Cox, R. D. et al., UKPDS 31: hepatocyte nuclear factor-1 alpha (the MODY3 gene) mutations in late onset type II diabetic patients in the United Kingdom: United Kingdom prospective diabetes study. Diabetologia, 1999, 42, 120–121.

  • Bellanne-Chantelot, C. et al., Clinical characteristics and diagnostic criteria of maturity-onset diabetes of the young (MODY) due to molecular anomalies of the HNF1A gene. J. Clin. Endocrinol. Metab., 2011, 96, E1346–E1351.

  • Steele, A. M. et al., Increased all-cause and cardiovascular mortality in monogenic diabetes as a result of mutations in the HNF1A gene. Diabet Med., 2010, 27, 157–161.

  • Carette, C. et al., Familial young-onset forms of diabetes related to HNF4A and rare HNF1A molecular aetiologies. Diabet. Med., 2010, 27, 1454–1458.

  • Herman, W. H. et al., Abnormal insulin secretion, not insulin resistance, is the genetic or primary defect of MODY in the RW pedigree. Diabetes, 1994, 43, 40–46.

  • Pearson, E. R. et al., Genetic cause of hyperglycaemia and response to treatment in diabetes. Lancet, 2003, 362, 1275–1281.

  • Shepherd, M., Shields, B., Ellard, S., Rubio-Cabezas, O. and Hattersley, A. T., A genetic diagnosis of HNF1A diabetes alters treatment and improves glycaemic control in the majority of insulintreated patients. Diabet. Med., 2009, 26(4), 437–441.

  • Pearson, E. R., Liddell, W. G., Shepherd, M., Corrall, R. J., Hattersley, A. T., Sensitivity to sulphonylureas in patients with hepatocyte nuclear factor-1 alpha gene mutations: evidence for pharmacogenetics in diabetes. Diabet Med., 2000, 17(7), 543–545.

  • Oliver-Krasinski, J. M. and Stoffers, D. A., On the origin of the B cell. Genes Dev., 2008, 22(15), 1998–2021.

  • Ahlgren, U., Jonsson, J., Jonsson, L., Simu, K. and Edlund, H., 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), 1763–1768.

  • Stoffers, D. A., Zinkin, N. T., Stanojevic, V., Clarke, W. L. and Habener, J. F., Pancreatic agenesis attributable to a single nucleotide deletion in the human IPF1 gene coding sequence. Nat. Genet., 1997, 15(1), 106–110.

  • Bellanné-Chantelot, C. et al., Clinical spectrum associated with hepatocyte nuclear factor-1 beta mutations. Ann. Intern. Med., 2004, 140, 510–517.

  • Chen, Y. Z. et al., Systematic review of TCF2 anomalies in renal cysts and diabetes syndrome/maturity onset diabetes of the young type 5. Chin. Med. J., 2010, 123(22), 3326–3333.

  • Clissold, R. L., Hamilton, A. J., Hattersley, A. T., Ellard, S. and Bingham, C., HNF1B-associated renal and extra-renal disease-an expanding clinical spectrum. Nat. Rev. Nephrol., 2015, 11(2), 102–112; doi:10.1038/nrneph.2014.232.

  • Edghill, E. L. et al., HLA genotyping supports a nonautoimmune etiology in patients diagnosed with diabetes under the age of 6 months. Diabetes, 2006, 55(6), 1895–1898.

  • Edghill, E. L. et al., Insulin mutation screening in 1044 patients with diabetes: mutations in the INS gene are a common cause of neonatal diabetes but a rare cause of diabetes diagnosed in childhood or adulthood. Diabetes, 2008, 57(4), 1034–1042.

  • Heidet, L. et al., Spectrum of HNF1B mutations in a large cohort of patients who harbor renal diseases. Clin. J. Am. Soc. Nephrol., 2010, 5, 1079–1090.

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

  • Brackenridge, A., Pearson, E. R., Shojaee-Moradie, F., Hattersley, A. T., Russell-Jones, D. and Umpleby, A. M., Contrasting insulin sensitivity of endogenous glucose production rate in subjects with hepatocyte nuclear factor-1 beta and -1 alpha mutations. Diabetes. 2006, 55(2), 405–411.

  • Naya, F. J. et al., Diabetes, defective pancreatic morphogenesis, and abnormal enteroendocrine differentiation in BETA2/neuro D-deficient mice. Genes Dev., 1997, 11(18), 2323–2334.

  • Kristinsson, S. Y. et al., MODY in Iceland is associated with mutations in HNF-1A and a novel mutation in NeuroD1. Diabetologia, 2001, 44(11), 2098–2103.

  • Rubio-Cabezas, O. et al., Homozygous mutations in NEUROD1 are responsible for a novel syndrome of permanent neonatal diabetes and neurological abnormalities. Diabetes, 2010, 59, 2326–2331.

  • Fernandez-Zapico, M. E. et al., MODY7 gene, KLF11, is a novel p300-dependent regulator of Pdx-1 (MODY 4) transcription in pancreatic islet beta cells. J. Biol. Chem., 2009, 284, 36482–36490.

  • Raeder, H. et al., Mutations in the CEL VNTR cause a syndrome of diabetes and pancreatic exocrine dysfunction. Nat. Genet., 2006, 38, 54–62.

  • Torsvik, J. et al., Mutations in the VNTR of the carboxyl-ester lipase gene (CEL) are a rare cause of monogenic diabetes. Hum. Genet., 2010, 127, 55–64.

  • Borowiec, M. et al., Mutations at the BLK locus linked to maturity onset diabetes of the young and beta-cell dysfunction. Proc. Natl. Acad. Sci. USA, 2009, 106, 14460–14465.

  • Støy, J., Steiner, D. F., Park, S. Y., Ye, H., Philipson, L. H. and Bell, G. I., Clinical and molecular genetics of neonatal diabetes due to mutations in the insulin gene. Rev. Endocr. Metab. Disord., 2010, 11(3), 205–215.

  • Molven, A. et al., Mutations in the insulin gene can cause MODY and autoantibody-negative type 1 diabetes. Diabetes, 2008, 57(4), 1131–1135.

  • Dusatkova, L. et al., Frame shift mutations in the insulin gene leading to prolonged molecule of insulin in two families with maturityonset diabetes of the young. Eur. J. Med. Genet., 2015, 58(4), 230–234.

  • Smith, S. B., Ee, H. C., Conners, J. R. and German, M. S., Pairedhomeodomain transcription factor PAX4 acts as a transcriptional repressor in early pancreatic development. Molec Cell Biol., 1999, 19(12), 8272–8280.

  • Plengvidhya, N. et al., PAX4 mutations in Thais with maturity onset diabetes of the young. J. Clin. Endocrinol. Metab., 2007, 92(7), 2821–2826.

  • Docena, M. K., Faiman, C., Stanley, C. M. and Pantalone, K. M., Mody-3: novel HNF1A mutation and the utility of glucagon- like peptide (GLP)-1 receptor agonist therapy. Endocr. Pract., 2014, 20(2), 107–111.

  • Østoft, S. H. et al., Glucose-lowering effects and low risk of hypoglycemia in patients with maturity-onset diabetes of the young when treated with a GLP-1 receptor agonist: a double-blind, randomized, crossover trial. Diabetes Care. 2014, 37(7), 1797–1805.

  • Lefèbvre, P. J., Paquot, N. and Scheen, A. J., Inhibiting or antagonizing glucagon: making progress in diabetes care. Diabetes Obes. Metab., 2015, 17(8), 720–725.

  • Yang, Y. and Chan, L., Monogenic diabetes: what it teaches us on the common forms of type 1 and type 2 diabetes. Endocrine Rev., 2016, 37(3), 190–222.

  • Prudente, S., Loss-of-function mutations in APPL1 in familial diabetes mellitus. Am. J. Hum. Genetics, 2010, 97, 177–185.

  • Mackay, D. J. G. and Temple, I. K., Transient neonatal diabetes mellitus type 1. Am. J. Med. Genet. C Semin. Med. Genet., 2010, 154(3), 335–342.

  • Steck, A. K. and Winter, W. E., Review on monogenic diabetes. Curr. Opin. Endocrinol. Diabetes Obes., 2011, 18(4), 252–258.

  • Flanagan, S. E. et al., Mutations in ATP-sensitive K+ channel genes cause transient neonatal diabetes and permanent diabetes in childhood or adulthood. Diabetes, 2007, 56, 1930–1937.

  • Gloyn, A. L. et al., Activating mutations in the gene encoding the ATP-sensitive potassium-channel subunit Kir6.2 and permanent neonatal diabetes. N. Engl. J. Med., 2004, 350, 1838–1849.

  • Babenko, A. P. et al., Activating mutations in the ABCC8 gene in neonatal diabetes mellitus. N. Engl. J. Med., 2006, 355(5), 456–466.

  • Proks, P. J. et al., A heterozygous activating mutation in the sulphonylurea receptor SUR1 (ABCC8) causes neonatal diabetes. Hum. Mol. Genet., 2006, 15(11), 1793–1800.

  • Thomas, P. M. et al., Mutations in the sulfonylurea receptor gene in familial persistent hyperinsulinemic hypoglycemia of infancy. Science, 1995, 268, 426–429.

  • Thomas, P. M., Cote, G. J., Wohllk, N., Mathew, P. M. and Gagel, R. F., The molecular basis for familial persistent hyperinsulinemic hypoglycemia of infancy. Proc. Assoc. Am. Physicians, 1996, 108(1), 14–19.

  • Rubio-Cabezas, O., Flanagan, S. E., Damhuis, A., Hattersley, A. T. and Ellard, S., KATP channel mutations in infants with permanent diabetes diagnosed after 6 months of life. Pediatr Diabetes, 2012, 13(4), 322–325.

  • Masia, R. et al., An ATP-binding mutation G334D in KCNJ11 is associated with a sulfonylurea-insensitive form of developmental delay, epilepsy, and neonatal diabetes. Diabetes, 2007, 56(2), 328–336.

  • Shimomura, K. et al., Adjacent mutations in the gating loop of Kir6.2 produce neonatal diabetes and hyperinsulinism. EMBO Mol. Med., 2009, 1(3), 166–177.

  • Pearson, E. R. et al., Switching from insulin to oral sulfonylureas in patients with diabetes due to Kir6.2 mutations. N. Engl. J. Med. 2006, 355, 467–477.

  • Rafiq, M., Flanagan, S. E., Patch, A. M., Shields, B. M., Ellard, S. and Hattersley, A. T., Effective treatment with oral sulfonylureas in patients with diabetes due to sulfonylurea receptor 1 SUR1 mutations. Diab. Care, 2008, 31(2), 204–209.

  • Hattersley, A. T., Beyond the beta cell in diabetes. Nature Genet., 2006, 38, 12–13.

  • Hattersley, A. T. and Pearson, E. R., Mini review: pharmacogenetics and beyond: the interaction of therapeutic response, beta-cell physiology, and genetics in diabetes. Endocrinology, 2006, 147, 2657–2663.

  • Distefano, J. K. and Watanabe, R. M., Pharmacogenetics of antidiabetes drugs. Pharmaceuticals (Basel), 2010, 3(8), 2610–2646.

  • Radha, V. et al., Identification of novel variants in the hepatocyte nuclear factor 1 alpha gene in South Indian patients with maturity onset diabetes of young. J. Clin. Endocr. Metabol., 2009, 94(6), 1959–1965.

  • Balamurugan, K. et al., Structure–function studies of HNF1A (MODY3) gene mutations in South Indian patients with monogenic diabetes. Clin. Genet., 2016 90(6), 486–495; doi:10.1111/cge.12757.

  • Anuradha, S., Radha, V. and Mohan, V., Association of novel variants in the hepatocyte nuclear factor 4A gene with maturity onset diabetes of the young and early onset type-2 diabetes. Clin. Genet., 2010, 80, 541–549.

  • Kanthimathi, S. et al., Glucokinase gene mutations (mody2) in Asian Indians. Diabetes Technol. Ther., 2014, 16(3), 180–185.

  • Kanthimathi, S. et al., Identification and functional characterization of hepatocyte nuclear factor-1B (MODY 5) gene mutations in Indian diabetic patients with renal abnormalities. Ann. Human Genetics, 2015, 79(1), 10–19.

  • Chapla, A. et al., Maturity onset diabetes of the young in India – a distinctive mutation pattern identified through targeted next-generation sequencing. Clin. Endocrinol.. 2015, 82(4), 533–542.

  • Aggarwal, V. et al., The renal cysts and diabetes (RCAD) syndrome in a child with deletion of the hepatocyte nuclear factor-1β gene. Indian J. Pediatr., 2010, 77(12), 1429–1431.

  • Doddabelavangala, M. 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:10.1371/journal.pone.0168656.

  • Letha, S. et al., Permanent neonatal diabetes mellitus due to KCNJ11 gene mutation. Indian J. Pediatr., 2007, 74(10), 947–949.

  • Ahamed, A. et al., Permanent neonatal diabetes mellitus due to a C96Y heterozygous mutation in the insulin cene. A case report. J. Pancreas, 2008, 9(6), 715–718.

  • Khadilkar, V. V., Khadilkar, A. V., Kapoor, R. R., Hussain, K., Hattersley, A. T. and Ellard, S., KCNJ11 activating mutation in an Indian family with remitting and relapsing diabetes. Indian J. Pediatr., 2010, 77(5), 551–554.

  • Kochar, I. P. S. and Kulkarni, K. P., Transient neonatal diabetes due to KCNJ11 Mutation. Indian Pediatrics, 2010, 47, 359–360.

  • Joshi, R. and Phatarpekar, A., Neonatal diabetes mellitus due to L233F mutation in the KCNJ11 gene. World J. Pediatr., 2011, 7(4), 371–372.

  • Jain, V., Flanagan, S. E. and Ellard, S., Permanent neonatal diabetes caused by a novel mutation. Indian Pediatr., 2012; 49(6), 486–488.

  • Jahnavi, S. et al., Clinical and molecular characterization of neonatal diabetes and monogenic syndromic diabetes in Asian Indian children. Clin. Genet., 2013, 83, 439–445.

  • Jahnavi, S. et al., Novel ABCC8 (SUR1) gene mutations in Asian Indian children with Congenital hyperinsulinemic hypoglycemia. Ann. Hum. Genetics, 2014, 78, 311–319.

  • De Leon, D. D. and Stanley, C. A., Mechanisms of disease: advances in diagnosis and treatment of hyperinsulinism in neonates. Nature Clin. Pract. Endocrinol. Metab., 2007, 3(1), 57–68.

  • Palladino, A. A., Bennett, M. J. and Stanley, C. A., Hyperinsulinism in infancy and childhood: when an insulin level is not always enough. Clin. Chem., 2008, 54(2), 256–263.


Abstract Views: 460

PDF Views: 135




  • Genetic Basis of Monogenic Diabetes

Abstract Views: 460  |  PDF Views: 135

Authors

V. Radha
Department of Molecular Genetics, Madras Diabetes Research Foundation, #20, Golden Jubilee Biotech Park for Women Society, SIPCOT, Siruseri, Chennai 603 103, India
V. Mohan
Department of Molecular Genetics, Madras Diabetes Research Foundation, #20, Golden Jubilee Biotech Park for Women Society, SIPCOT, Siruseri, Chennai 603 103, India

Abstract


Advances in the understanding of monogenic causes of diabetes and the discovery of single-gene mutations responsible for different phenotypes have greatly increased our knowledge of β-cell physiology. Such advances have had implications for the individual patient diagnosed with the specific monogenic cause of diabetes, especially in maturity onset diabetes of the young (MODY) and neonatal diabetes mellitus (NDM). Genetic diagnosis of MODY is also likely to have important prognostic and therapeutic implications in majority of the patients with confirmed HNF1A and HNF4A mutations. Genetic screening and analyses have helped several neonatal infants carrying mutations in the KCNJ11 and ABCC8 genes to shift from insulin treatment to oral sulphonylurea drugs. The progress in genomics of monogenic diabetic forms has helped in translating the discoveries from bench to bedside in clinical care. Therefore, there is an urgent need to incorporate genetic testing for the genes implicated in monogenic diabetes like MODY and NDM in the diabetes clinics. Discoveries in genetic research methodology and understanding of genetic etiology will have great translational implications for disease treatment and follow-up.

Keywords


Genetic Screening, Maturity Onset Diabetes of the Young, Monogenic Diabetes, Neonatal Diabetes, Precision Medicine.

References





DOI: https://doi.org/10.18520/cs%2Fv113%2Fi07%2F1277-1286