Novel variants in the hepatocyte nuclear factor-1-alpha gene in MODY and early onset NIDDM: Evidence for a mutational hotspot in exon 5

Abstract

The disorder, Maturity Onset of Diabetes of the young (MODY) is a monogenic form of Non-Insulin dependent Diabetes Mellitus (NIDDM), characterized by autosomal dominant mode of inheritance and onset is usually before 25 years of age. Clinical studies of subjects with the different forms of MODY indicate that each is associated with a different defect in the normal pattern of glucose stimulated insulin secretion. MODY can result from mutations in any one of the six different genes, one of which encodes the glycolytic enzyme Glucokinase, associated with MO-DY2 and the other five encode transcription factors HNF4-alpha associated with MODY 1, HNF1-alpha associated with MODY 3, IPF with MODY 4, HNF1-Beta with MODY 5 and NeuroD1 with MO-DY6. Studies related to mutations in the MODY genes have led to a better understanding of the genetic causes of the Beta cell dysfunction as genetic factors plays a great role in this disorder. Objective: To investigate the mutation pattern in the different transcription factor genes with special reference to HNF1-alpha which are highly penetrant with 63% mutation carriers manifesting clinical diabetes by the age of 25 years. Hence study of mutation pattern in this gene is essential in our population i.e. Eastern Indian population. Our study is focused on HNF1-alpha related to MODY 3, which is the most common one. Methods: In our study enzyme amplification (PCR) of the 10 target exons of the said gene with simultaneous mutation detection in them by PCR-SSCP (Polymerase chain reaction-single strand conformational polymorphism) reaction analysis method was attempted by screening of exon 1 - 10 with respect to normal healthy controls without Diabetes Mellitus. The nature of the specific mutations was also determined by sequencing. Result: It was observed that maximum number of variations exist in exon 5 of HNF1-alpha gene which may be referred to as “Mutational Hotspot” in our Eastern Indian population. Conclusions: Since maximum number of variations exists in exon 5 of the said gene, hence one can initially go for exon5 followed by other exons, while screening for pathogenic MODY 3 mutations in the responsible gene by PCR-SSCP method.

Share and Cite:

Ghosal, C. , Sen, A. , Chowdhury, S. , Pandit, K. , Banerjee, S. , Paine, S. , Chowdhury, S. and Bhattacharya, B. (2012) Novel variants in the hepatocyte nuclear factor-1-alpha gene in MODY and early onset NIDDM: Evidence for a mutational hotspot in exon 5. Open Journal of Preventive Medicine, 2, 116-122. doi: 10.4236/ojpm.2012.21017.

Conflicts of Interest

The authors declare no conflicts of interest.

References

[1] Mclntyre, E.A. and Walker, M. (2002) Genetics of type 2 diabetes and insulin resistance: Knowledge from human studies. Clinical Endocrinology, 57, 303-311.
[2] Winter, W.E. (2000) Molecular and biochemical analysis of the MODY Syndromes. Pediatric Diabetes, 1, 88-117. doi:10.1034/j.1399-5448.2000.010206.x
[3] Fajans, S.S. and Bell, G.I. (2001) Molecular mechanisms and clinical pathophysiology of maturity onset diabetes of the young. New England Journal of Medicines, 345, 971-980. doi:10.1056/NEJMra002168
[4] Elbein, S.C., Teng, K., Yount, P., et al. (1998).Linkage and molecular scaning analysis of MODY 3/hepatocyte nuclear factor 1-alpha gene in typical familial type 2 diabetes: Evidence for novel mutation in exon 8 and 10. Journal of Clinical Eendocrinology and Metabolism, 83, 2059-2065. doi:10.1210/jc.83.6.2059
[5] Froguel, P. and Velho, G. (1999) Molecular genetics of Maturity-onset Diabetes of the young. Trends Endocrinol Metab, 10, 142-146. doi:10.1016/S1043-2760(98)00134-9
[6] Hattersley, A.T. (1998) Maturity-onset diabetes of the young: Clinical heterogeneity explained by genetic heterogeneity. Diabetes Care, 15, 15-24.
[7] Lehto, M., Wipemo, C., Ivarsson, S.A., et al. (1999) High frequency of mutations in MODY and mitochondrial genes in Scandinavian patients with familial early-onset diabetes. Diabetologia, 42, 1131-1137. doi:10.1007/s001250051281
[8] Mohan, V., Ramachandran, A., Snehalatha, C., et al. (1985) High prevalence of maturity onset diabetes of the young (MODY) among Indians. Diabetes Care, 8, 371-374. doi:10.2337/diacare.8.4.371
[9] Sambroock, J., Fritsch, E.F. and Maniatis, T. (1989) Molecular cloning: A laboratory manual. Cold Spring Harbour Publishing, New York.
[10] Baroni, M.G., Sentinelli, F., Massa, O., et al. (2001) Single-strand conformation polymorphism analysis of the glucose transporter gene GLUT1 in maturity-onset diabetes of the young. Journal of Molecular Medicine, 79, 270-274. doi:10.1007/s001090100220
[11] Ellard, S. (2000) Hepatocyte nuclear factor 1 alpha (HNF-1 alpha) mutations in maturity-onset diabetes of the young. Human Mutation, 16, 377-385. doi:10.1002/1098-1004(200011)16:5<377::AID-HUMU1>3.0.CO;2-2
[12] Christine, B., Claire, C., Jean, R., et al. (2008) 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.
[13] Shih, D.Q. and Stoffel, M. (2002) Molecular etiologies of MODY and other early-onset forms of diabetes. Current Diabetes Reports, 2, 125-134. doi:10.1007/s11892-002-0071-9
[14] Radha, V., Ek, J., Anuradha, S., et al. (2009) Identification of novel variants in the hepatocyte nuclear factor-1α gene in South Indian patients with Maturity Onset Diabetes of Young. The Journal of Clinical Endocrinology & Metabolism, 94, 1959-1965. doi:10.1210/jc.2008-2371
[15] Byrne, M.M., Sturis, J., Menzel, S., et al. (1996) Altered insulin secretory responses to glucose in diabetic and non-diabetic subjects with mutations in the diabetes susceptibility gene MODY 3 on chromosome 12. Diabetes, 45, 1503-1510. doi:10.2337/diabetes.45.11.1503
[16] Vaxillaire, M., Rouard, M., Yamagata, K., et al. (1997) Identification of nine novel mutations in the hepatocyte nuclear factor-1 gene associated with maturity-onset diabetes of the young (MODY 3). Human Molecular Genetics, 6, 583-586. doi:10.1093/hmg/6.4.583
[17] Yamagata, K., Oda, N., Kaisaki, P.J., Menzel, S., et al. (1996) Mutations in the hepatocyte nuclear factor-1 alpha gene in maturity-onset diabetes of the young (MODY 3). Nature, 384, 455-458. doi:10.1038/384455a0
[18] Kaisaki, P.J., Menzel, S., Lindner, T., et al. (1997) Mutations in the hepatocyte nuclear factor-1-α gene in MODY and early-onset NIDDM. Evidence for a mutational hotspot in exon 4. Diabetes, 46, 528-535. doi:10.2337/diabetes.46.3.528
[19] Zhen, Y., Song-hua, W.U., Tai-Shan, Z., et al. (2006) Identification of four novel mutations in the HNF-1A gene in Chinese early-onset and/or multiplex diabetes pedigrees. The Journal of Chinese Medicine, 119, 1072-1078.
[20] Tonooka, N., Tomura, H., Takahashi, Y., et al. (2002), 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, 45, 1709-1712. doi:10.1007/s00125-002-0978-3
[21] Domínguez-López, A., Miliar-García, A., Segura-Kato, Y.X., et al. (2005) Mutations in MODY genes are not common cause of early-onset type 2 diabetes in Mexican families. JOP, 10, 238-245.

Copyright © 2024 by authors and Scientific Research Publishing Inc.

Creative Commons License

This work and the related PDF file are licensed under a Creative Commons Attribution 4.0 International License.