ORIGINAL ARTICLE

JOP. J Pancreas (Online) 2005; 6(2):238-245.

Mutations in MODY Genes Are not Common Cause of Early-Onset Type 2 Diabetes in Mexican Families

Aarón Domínguez-López1, Ángel Miliar-García1,2, Yayoi X Segura-Kato1, Laura Riba1, José Esparza-López1, Salvador Ramírez-Jiménez1, Maribel Rodríguez-Torres1, Samuel Canizales-Quinteros1, Siraam Cabrera-Vásquez1, Verónica Fragoso-Ontiveros1, Carlos A Aguilar-Salinas3, Nelly Altamirano-Bustamante4, Raúl Calzada-León4, Carlos Robles-Valdés4, Luz E Bravo-Ríos5, Maria Teresa Tusié-Luna1

1Molecular Biology and Genomic Medicine Unit, National Institute for Medical Sciences and Nutrition 'Salvador Zubirán' and Biomedical Research Institute at National Autonomous University of Mexico; 2Postgraduate Studies and Research Section, School of Medicine, National Polytechnic Institute; 3Endocrinology Department, National Institute for Medical Sciences and Nutrition 'Salvador Zubirán'; 4Pediatric Endocrinology Department, National Institute of Pediatrics; 5Pediatric Endocrinology Department, General Hospital Medical Center 'La Raza'. Mexico City, Mexico

ABSTRACT

Context Maturity-onset diabetes of the young (MODY) is a monogenic form of diabetes mellitus characterized by autosomal dominant inheritance, early age of onset and a primary insulin secretion defect. Certain MODY gene sequence variants may be involved in polygenic forms of type 2 diabetes.

Objetive We assessed the contribution of MODY genes to the etiology of type 2 early-onset diabetes in 23 Mexican families, including five with apparently autosomal dominant inheritance.

Patients Twenty-three unrelated Mexican families with early-onset type 2 diabetes previously screened for the presence of glucokinase mutations, were studied.

Design We screened MODY genes for sequence variants by PCR-SSCP analysis and automated sequencing. We performed a functional analysis of the HNF-1alpha P379H recombinant protein in vitro in both HeLa and RINm5f beta-cell lines.

Main outcome measures MODY gene mutation screening and P379H mutant protein transactivation assay.

Results No mutations were detected in the HNF-4alpha, IPF-1, NEUROD1 or HNF-1beta genes in any of the families studied. A new mutation (P379H) of the HNF-1alpha gene was identified in one MODY family. RINm5f and HeLa cell transfection assays revealed decreased transactivation activity of the mutant protein on the human insulin promoter.

Conclusions All known MODY genes were screened for abnormalities in this cohort of early-onset diabetes families which included 5 MODY pedigrees. We identified a new HNF-1alpha MODY mutation (P379H) and demonstrated that it reduces the transactivation potential of the mutant protein on the human insulin promoter. No other mutation was identified in this cohort indicating that abnormalities in MODY genes are generally not a common cause of early-onset diabetes and this includes MODY families in Mexico.

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References

  1. Zimmet P, Alberti KG, Shaw J. Global and social implications of the diabetic epidemic. Nature 2001; 414:782-7. [More details]

  2. Aguilar-Salinas CA, Rojas RF, Gómez-Pérez J, García E, Valles V, Ríos-Torres JM, et al. Prevalence and characteristic of early-onset type 2 diabetes in Mexico. Am J Med 2002; 113:569-74. [More details]

  3. Olaiz G, Rojas R, Barquera S, Shamah T, Aguilar C, Cravioto P, López P, Hernández M, Tapia R, Sepúlveda J. Encuesta Nacional de Salud 2000. Tomo 2. La Salud de los adultos.Cuernavaca Morelos, México Instituto Nacional de Salud Pública. [More details]

  4. Aguilar-Salinas CA, Velazquez Monroy O, Gomez-Perez FJ, Gonzalez Chavez A, Esqueda AL, Molina Cuevas V, et al. Characteristics of the patients with type 2 diabetes in Mexico: results from a large population-based, nation wide survey. Diabetes Care 2003; 26:2021-6. [More details]

  5. Froguel P, Zouali H, Vionnet N, Velho G, Vaxillaire M, Sun F, et al. Familial hyperglycemia due to mutations in glucokinase: definition of a subtype of diabetes mellitus. N Engl J Med1993; 328:697-702. [More details]

  6. Yamagata K, Furuta H, Oda N, Kaisaki PJ, Menzel S, Cox NJ, et al. Mutations in the hepatocyte nuclear factor-4 alpha gene in maturity-onset diabetes of the young (MODY1). Nature 1996; 384:458-60. [More details]

  7. Yamagata K, Oda N, Kaisaki PJ, Menzel S, Furuta H, Vaxillaire H, et al. Mutations in the hepatocyte nuclear factor-1 alpha gene in maturity-onset diabetes of the young (MODY3). Nature 1996; 384:455-8. [More details]

  8. Stoffers DA, Ferrer J, Clarke WL, Habener HL. Early-onset type- II diabetes (MODY4) linked to IPF-1. Nat Genet 1997; 17:138-9. [More details]

  9. Horikawa Y, Iwasaki N, Hara M, Furuta H, Hinokio Y, Cockburn BN, et al. Mutations in the hepatocyte nuclear factor-1 beta gene (TCF2) associated with MODY. Nat Genet 1997; 17:384-5. [More details]

  10. Malecki MT, Jhala US, Antonellis A, Fields L, Doria A, Orban T, et al. Mutations in NEUROD1 are associated with the development of type 2 diabetes mellitus. Nat Genet 1999; 23:323-8. [More details]

  11. Velho G, Robert JJ. Maturity-Onset Diabetes of the Young (MODY): Genetic and Clinical Characteristics. Horm Res 2002; 57:29-33. [More details]

  12. Triggs-Raine BL, Kirkpatrick RD, Kelly SL, Norquay LD, Cattini PA, Yamagata K, et al. HNF-1alpha G319S, a transactivation-deficient mutant, is associated with altered dynamics of diabetes onset in an Oji-Cree community. Proc Natl Acad Sci USA 2002; 99:4614-9. [More details]

  13. Hani EH, Suaud L, Boutin P, Chevre JC, Durand E, Philippi A, et al. A missense mutation in hepatocyte nuclear factor-4 alpha, resulting in a reduced transactivation activity, in human late-onset non-insulin-dependent diabetes mellitus. J Clin Invest 1998; 101:521-6. [More details]

  14. Sakurai K, Seki N, Fujii R, Yagui K, Tokuyama Y, Shimada F, et al. Mutations in the hepatocyte nuclear factor-4alpha gene in Japanese with non-insulin-dependent diabetes: a nucleotide substitution in the polypyrimidine tract of intron 1b. Horm Metab Res 2000; 32:316-20. [More details]

  15. Macfarlane WM, Frayling TM, Ellard S, Evans JC, Allen LI, Bulman MP, et al. Missense mutations in the insulin promoter factor-1 gene predispose to type 2 diabetes. J Clin Invest 1999; 104:R33-9. [More details]

  16. Del Bosque-Plata L, García-García E, Ramírez-Jiménez S, Cabello-Villegas J, Riba L, Gomez-León A. et al. Analysis of the glucokinase gene in Mexican families displaying early-onset non-insulin dependent diabetes mellitus including MODY families. Am J Med Genet 1997; 72:387-93. [More details]

  17. Lehto M, Wipemo C, Ivarsson SA, Linfgren C, Lipsanen-Nyman M, Weng J. et al. High frequency of mutations in MODY and mitochondrial genes in Scandinavian patients with familial early-onset diabetes. Diabetologia 1999; 42:1131-7. [More details]

  18. Thomas H, Jaschkowitz K, Bulman M, Frayling TM, Mitchell SMS, Roosen S, et al A distant upstream promoter of the HNF-4alphagene connects the transcription factors involved in maturity-onset diabetes of the young. Hum Mol Genet 2001; 10:2089-97. [More details]

  19. Ellard S. Hepatocyte nuclear factor 1 alpha (HNF-1 alpha) mutations in maturity-onset diabetes of the young. Hum Mut 2000; 16:377-85. [More details]

  20. Shih DQ, Stoffel M. Molecular etiologies of MODY and other early-onset forms of diabetes. Curr Diab Rep 2002; 2:125-34. [More details]

  21. Frayling TM, Evans JC, Bulman MP, Pearson E, Allen L, Owen K, et al. Beta-cell genes and diabetes: molecular and clinical characterization of mutations in transcription factors. Diabetes 2001; 50:S94. [More details]

  22. Barrio R, Bellanne-Chantelot C, Moreno JC, Morel V, Calle H, Alonso M, Mustieles C. Nine novel mutations in Maturity-Onset Diabetes of the Young (MODY) Candidate genes in 22 Spanish families. J Clin Endo Metab 2002; 87:2532-9. [More details]

  23. Pruhova S, Ek J, Lebl J, Sumnik Z, Saudek F, Andel M, et al. Genetic epidemiology of MODY in the Czech republic: new mutations in the MODY genes HNF-4alpha, GCK and HNF-1alpha. Diabetologia 2003; 46:291-5. [More details]

  24. Tonooka N, Tomura H, Takahashi Y, Onigata K, Kikuchi N, Horikawa 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; 45:1709-12. [More details]

  25. Bjorkhaug L, Sagen JV, Thorsby P, Sovik O, Molven A, Njolstad PR Hepatocyte nuclear factor-1 alpha gene mutations and diabetes in Norway. J Clin Endocrinol Metab 2003; 88:920-31. [More details]

  26. Velho G, Froguel P. Genetic, metabolic and clinical characteristics of maturity onset diabetes of the young. EurJ Endocrinol 1998; 138:233-9. [More details]

  27. Frayling TM, Lingren CM, Chevre JC, Menzel S, Wishart M, Benmerzroua Y, et al. A genome-wide scan in families with maturity-onset diabetes of the young. Diabetes 2003; 52:872-81. [More details]

  28. Kim SH, Ma X, Weremowicz S, Ercolino T, Powers C, Mlynarski W, et al. Identification of a locus for maturity-onset diabetes of the young on chromosome 8p23. Diabetes 2004; 53:1375-84. [More details]

  29. Hayashi K, Yandell DW. How sensitive is PCR-SSCP? Hum Mutat 1993; 2:338-46. [More details]

  30. Bunn CF, Lintott CJ, Scott RS, George PM. Comparison of SSCP and DHPLC for the detection of LDLR mutations in a New Zealand cohort. Hum Mutat 2002, 19:311-3. [More details]

  31. Fan E, Levin DB, Glickman BW, Logan DM. Limitations in the use of SSCP analysis Mutat Res 1993; 283:85-92. [More details]

  32. Moises SR, Reis AF, Morel V. Prevalence of Maturity-onset diabetes of the young mutations in Brazilian families with autosomal dominant early-onset type 2 diabetes. Diabetes Care 2001; 24:786-7. [More details]

  33. Allayee H, Parker D, Stammreich A, Canales J, Scheel G, Lusis A, Ipp E. Mutations in the genes for MODY are not a common cause of early-onset type 2 diabetes in minority populations. American Society of Human Genetics, Annual Meeting 2004 Abstract 2177. [More details]

Keywords Genetics; Mexico; Polymorphism, Genetic

Correspondence Maria Teresa Tusié-Luna:tusie@servidor.unam.mx