Identification of novel variants in HNF1-alpha gene in maturity onset diabetes in young adults (MODY) subjects of Eastern India

Background: 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 the 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 as of now, one of which encodes the glycolytic enzyme Glucokinase, associated with MODY2 and the other five encode transcription factors HNF4alpha associated with MODY1,HNF1alpha associated with MODY3, IPF with MODY4, HNF1Beta with MODY5 and NeuroD1 with MODY6.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 play a great role in this disorder. Objective: To investigate the mutation pattern/patterns in the different transcription factor genes with special reference to HNF1alpha gene 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 HNF1alpha related to MODY3, which is the most common one. Methods: In our study, the enzyme amplification (PCR) of the10 target exons of the said gene with simultaneous mutation detection in them by PCR-SSCP (Polymerase chain reaction followed by single strand conformational polymorphism) reaction analysis method was attempted by screening of exon1-10 with respect to normal healthy controls without Diabetes Mellitus. The nature of the specific mutations was also determined by sequencing. Result: It was observed in our study that there were sequence variants existing in exon7 and exon 8 of HNF1-alpha gene, revealed by PCR-SSCP study in our population which goes in agreement with the sequencing study. The age at diagnosis of the subjects with novel single base substitution polymorphisms in exon 7 seem to be little less than those in subjects with polymorphisms in exon 8 of the HNF1-alpha gene. Conclusions: The age at diagnosis of the subjects with novel single base substitution polymorphisms in exon 7 seem to be little less than that in subjects with polymorphisms in exon 8 of the HNF1-alpha gene, emphasizing that age at diagnosis is influenced by variations in mutational positions.