Molecular genetics of monogenetic beta-cell diabetes

Authors

  • Jatuporn Sujjitjoon Department of Immunology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok 10700, Thailand.
  • Prapaporn Jungtrakoon Department of Immunology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok 10700, Thailand.
  • Watip Boonyasrisawat Department of Immunology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok 10700, Thailand.
  • Nalinee Chongjaroen Department of Immunology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok 10700, Thailand.
  • Titikan Chukijrungroat Department of Physiology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok 10700, Thailand.
  • Suwattanee Kooptiwut Department of Physiology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok 10700, Thailand.
  • Nattachet Plengvidhya Division of Endocrinology and Metabolism, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok 10700, Thailand.
  • Napatawn Banchuin Department of Immunology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok 10700, Thailand.
  • Pa-thai Yenchitsomanus Division of Medical Molecular Biology, Department of Research and Development, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok 10700, Thailand.

Keywords:

Monogenic diabetes, -cell dysfunction, neonatal diabetes mellitus, maturity-onset diabetes of the young, early-onset type 2 diabetes, mitochondrial diabetes, transcription factor, hepatocyte nuclear factor

Abstract

Monogenic b-cell diabetes – a rare form of diabetes mellitus (DM) is caused by defects in a group of genes controlling pancreatic b-cell development and function. The diabetic symptoms are manifested within a short period after birth as neonatal diabetes mellitus (NDM), in childhood or early adulthood as maturity-onset diabetes of the young (MODY) and mitochondrial diabetes. Several etiologic genes for this form of DM have been identified in many patients. The common etiologic genes encode b-cell transcription factors and proteins involving in glucose-stimulated insulin secretion. Owning to their nature of genetic heterogeneity, monogenic b-cell diabetes presents the characteristics of variable age at onset, degree of severity, and occurrence of diabetic complications. The study of this form of diabetes has provided new knowledge and a better insight into the molecular mechanism controlling normal and pathological states of b-cells as reviewed in this article.

References

Bellanne-Chantelot, C., Clauin, S., Chauveau, D., Collin, P., Daumont, M., Douillard, C., Dubois-Laforgue, D., Dusselier, L., Gautier, J. F., Jadoul, M., Laloi-Michelin, M., Jacquesson, L., Larger, E., Louis, J., Nicolino, M., Subra, J. F., Wilhem, J. M., Young, J., Velho, G., and Timsit, J. 2005. 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 54: 3126-3132.

Bellanne-Chantelot, C., Carette, C., Riveline, J. P., Valero, R., Gautier, J. F., Larger, E., Reznik, Y., Ducluzeau, P. H., Sola, A., Hartemann-Heurtier, A., Lecomte, P., Chaillous, L., Laloi-Michelin, M., Wilhem, J. M., Cuny, P., Duron, F., Guerci, B., Jeandidier, N., Mosnier-Pudar, H., Assayag, M., Dubois-Laforgue, D., Velho, G., and Timsit, J. 2007. 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 57: 503-508.

Carette, C., Vaury, C., Barthelemy, A., Clauin, S., Grunfeld, J. P., Timsit, J., and Bellanne-Chantelot, C. 2007. Exonic duplication of the hepatocyte nuclear factor-1beta gene (transcription factor 2, hepatic) as a cause of maturity onset diabetes of the young type 5. J Clin Endocrinol Metab 92: 2844-2847.

Edghill, E. L., Bingham, C., Ellard, S., and Hattersley, A. T. 2006. Mutations in hepatocyte nuclear factor-1beta and their related phenotypes. J Med Genet 43: 84-90.

Ek, J., Hansen, S. P., Lajer, M., Nicot, C., Boesgaard, T. W., Pruhova, S., Johansen, A., Albrechtsen, A., Yderstraede, K., Lauenborg, J., Parrizas, M., Boj, S. F., Jorgensen, T., Borch-Johnsen, K., Damm, P., Ferrer, J., Lebl, J., Pedersen, O., and Hansen, T. 2006. A novel -192c/g mutation in the proximal P2 promoter of the hepatocyte nuclear factor-4 alpha gene (HNF4A) associates with late-onset diabetes. Diabetes 55: 1869-1873.

Fajans, S. S. and Conn, J. W. 1960. Tolbutamide-induced improvement in carbohydrate tolerance of young people with mild diabetes mellitus. Diabetes 9: 83-88.

Fajans, S. S., Bell, G. I. and Polonsky, K. S. 2001. Molecular mechanisms and clinical pathophysiology of maturity-onset diabetes of the young. N Engl J Med 345: 971-980.

Garcia-Herrero, C. M., Galan, M., Vincent, O., Flandez, B., Gargallo, M., Delgado-Alvarez, E., Blazquez, E., and Navas, M. A. 2007. Functional analysis of human glucokinase gene mutations causing MODY2: exploring the regulatory mechanisms of glucokinase activity. Diabetologia 50: 325-333.

Glaser, B., Kesavan, P., Heyman, M., Davis, E., Cuesta, A., Buchs, A., Stanley, C. A., Thornton, P. S., Permutt, M. A., Matschinsky, F. M., and Herold, K. C. 1998. Familial hyperinsulinism caused by an activating glucokinase mutation. N Engl J Med 338: 226-230.

Gloyn, A. L. 2003. Glucokinase (GCK) mutations in hyper- and hypoglycemia: maturity-onset diabetes of the young, permanent neonatal diabetes, and hyperinsulinemia of infancy. Hum Mutat 22: 353-362.

Gragnoli, C., Stanojevic, V., Gorini, A., Von Preussenthal, G. M., Thomas, M. K., and Habener, J. F. 2005. IPF-1/MODY4 gene missense mutation in an Italian family with type 2 and gestational diabetes. Metabolism 54: 983-988.

Gragnoli, C., Lindner, T., Cockburn, B. N., Kaisaki, P. J., Gragnoli, F., Marozzi, G., and Bell, G. I. 1997. Maturity-onset diabetes of the young due to a mutation in the hepatocyte nuclear factor-4 alpha binding site in the promoter of the hepatocyte nuclear factor-1 alpha gene. Diabetes 46: 1648-1651.

Hattersley A. T. 2003. Maturity-onset diabetes of the young, pp. 24.1-24.12. In: Pickup JC, Williams G, (eds.) Textbook of Diabetes. 3rd ed., Oxford, UK. Blackwell Publishing company.

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

Horikawa, Y., Iwasaki, N., Hara, M., Furuta, H., Hinokio, Y., Cockburn, B. N., Lindner, T., Yamagata, K., Ogata, M., Tomonaga, O., Kuroki, H., Kasahara, T., Iwamoto, Y., and Bell, G. I. 1997. Mutation in hepatocyte nuclear factor-1 beta gene (TCF2) associated with MODY. Nat Genet 17: 384-385.

Kadowaki, T., Kadowaki, H., Mori, Y., Tobe, K., Sakuta, R., Suzuki, Y., Tanabe, Y., Sakura, H., Awata, T., Goto, Y., and et al. 1994. A subtype of diabetes mellitus associated with a mutation of mitochondrial DNA. N Engl J Med 330: 962-968.

Kim, K. A., Kang, K., Chi, Y. I., Chang, I., Lee, M. K., Kim, K. W., Shoelson, S. E., and Lee, M. S. 2003. Identification and functional characterization of a novel mutation of hepatocyte nuclear factor-1alpha gene in a Korean family with MODY3. Diabetologia 46: 721-727.

Kim, S. H., Ma, X., Weremowicz, S., Ercolino, T., Powers, C., Mlynarski, W., Bashan, K. A., Warram, J. H., Mychaleckyj, J., Rich, S. S., Krolewski, A. S., and Doria, A. 2004. Identification of a locus for maturity-onset diabetes of the young on chromosome 8p23. Diabetes 53: 1375-1384.

Kobayashi, T., Nakanishi, K., Nakase, H., Kajio, H., Okubo, M., Murase, T., and Kosaka, K. 1997. In situ characterization of islets in diabetes with a mitochondrial DNA mutation at nucleotide position 3243. Diabetes 46: 1567-1571.

Kristinsson, S. Y., Thorolfsdottir, E. T., Talseth, B., Steingrimsson, E., Thorsson, A. V., Helgason, T., Hreidarsson, A. B., and Arngrimsson, R. 2001. MODY in Iceland is associated with mutations in HNF-1alpha and a novel mutation in NeuroD1. Diabetologia 44: 2098-2103.

Lehto, M., Bitzen, P. O., Isomaa, B., Wipemo, C., Wessman, Y., Forsblom, C., Tuomi, T., Taskinen, M. R., and Groop, L. 1999. Mutation in the HNF-4alpha gene affects insulin secretion and triglyceride metabolism. Diabetes 48: 423-425.

Liu, L., Furuta, H., Minami, A., Zheng, T., Jia, W., Nanjo, K., and Xiang, K. 2007. A novel mutation, Ser159Pro in the NeuroD1/BETA2 gene contributes to the development of diabetes in a Chinese potential MODY family. Mol Cell Biochem 303: 115-120.

Murphy, R., Ellard, S., and Hattersley, A. T. 2008. Clinical implications of a molecular genetic classification of monogenic beta-cell diabetes. Nat Clin Pract Endocrinol Metab 4: 200-213.

Naya, F. J., Stellrecht, C. M., and Tsai, M. J. 1995. Tissue-specific regulation of the insulin gene by a novel basic helix-loop-helix transcription factor. Genes Dev 9: 1009-1019.

Pearson, E. R., Velho, G., Clark, P., Stride, A., Shepherd, M., Frayling, T. M., Bulman, M. P., Ellard, S., Froguel, P., and Hattersley, A. T. 2001. beta-cell genes and diabetes: quantitative and qualitative differences in the pathophysiology of hepatic nuclear factor-1alpha and glucokinase mutations. Diabetes 50 Suppl 1: S101-107.

Plengvidhya, N., Kooptiwut, S., Songtawee, N., Doi, A., Furuta, H., Nishi, M., Nanjo, K., Tantibhedhyangkul, W., Boonyasrisawat, W., Yenchitsomanus, P, Doria, A., and Banchuin, N. 2007. PAX4 mutations in Thais with maturity onset diabetes of the young. J Clin Endocrinol Metab 92: 2821-2826.

Plengvidhya, N., Boonyasrisawat, W., Chongjaroen, N., Jungtrakoon, P., Sriussadaporn, S., Vannaseang, S., Banchuin, N., Yechitsomanus, P. 2008. Mutations of maturity-onset diabetes of the young (MODY) genes in Thais with early-onset type 2 Diabetes mellitus. Clin Endoclinol. Manuscript in press

Rey-Campos, J., Chouard, T., Yaniv, M., and Cereghini, S. 1991. vHNF1 is a homeoprotein that activates transcription and forms heterodimers with HNF1. Embo J 10: 1445-1457.

Sharma, A., Moore, M., Marcora, E., Lee, J. E., Qiu, Y., Samaras, S., and Stein, R. 1999. The NeuroD1/BETA2 sequences essential for insulin gene transcription colocalize with those necessary for neurogenesis and p300/CREB binding protein binding. Mol Cell Biol 19: 704-713.

Shih, D. Q., Dansky, H. M., Fleisher, M., Assmann, G., Fajans, S. S., and Stoffel, M. 2000. Genotype/phenotype relationships in HNF-4alpha/MODY1: haploinsufficiency is associated with reduced apolipoprotein (AII), apolipoprotein (CIII), lipoprotein(a), and triglyceride levels. Diabetes 49: 832-837.

Stoffel, M. and Duncan, S. A. 1997. The maturity-onset diabetes of the young (MODY1) transcription factor HNF4alpha regulates expression of genes required for glucose transport and metabolism. Proc Natl Acad Sci USA 94: 13209-13214.

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

Tamimi, R., Steingrimsson, E., Copeland, N. G., Dyer-Montgomery, K., Lee, J. E., Hernandez, R., Jenkins, N. A., and Tapscott, S. J. 1996. The NEUROD gene maps to human chromosome 2q32 and mouse chromosome 2. Genomics 34: 418-421.

The Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. 2003. Report of the expert committee on the diagnosis and classification of diabetes mellitus. Diabetes Care 26 Suppl. 1: S5-20.

Winter, W. E. 2000. Molecular and biochemical analysis of the MODY syndromes. Pediatr Diabetes 1: 88-117.

Wright, N. M., Metzger, D. L., Borowitz, S. M., and Clarke, W. L. 1993. Permanent neonatal diabetes mellitus and pancreatic exocrine insufficiency resulting from congenital pancreatic agenesis. Am J Dis Child 147: 607-609.

Yamagata, K., Furuta, H., Oda, N., Kaisaki, P. J., Menzel, S., Cox, N. J., Fajans, S. S., Signorini, S., Stoffel, M., and Bell, G. I. 1996a. Mutations in the hepatocyte nuclear factor-4alpha gene in maturity-onset diabetes of the young (MODY1). Nature 384: 458-460.

Yamagata, K., Oda, N., Kaisaki, P. J., Menzel, S., Furuta, H., Vaxillaire, M., Southam, L., Cox, R. D., Lathrop, G. M., Boriraj, V. V., Chen, X., Cox, N. J., Oda, Y., Yano, H., Le Beau, M. M., Yamada, S., Nishigori, H., Takeda, J., Fajans, S. S., Hattersley, A. T., Iwasaki, N., Hansen, T., Pedersen, O., Polonsky, K. S., Bell, G. I., and et al. 1996b. Mutations in the hepatocyte nuclear factor-1alpha gene in maturity-onset diabetes of the young (MODY3). Nature 384: 455-458.

Yamagata, K. 2003. Regulation of pancreatic beta-cell function by the HNF transcription network: lessons from maturity-onset diabetes of the young (MODY). Endocr J 50: 491-499.

Yang, Q., Yamagata, K., Yamamoto, K., Miyagawa, J., Takeda, J., Iwasaki, N., Iwahashi, H., Yoshiuchi, I., Namba, M., Miyazaki, J., Hanafusa, T., and Matsuzawa, Y. 1999. Structure/function studies of hepatocyte nuclear factor-1alpha, a diabetes-associated transcription factor. Biochem Biophys Res Commun 266: 196-202.

Downloads

Published

2012-07-12

Issue

Vol. 1 No. 2 (2008): July-Dec 2008

Section

Research Articles