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

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 MODY2 and the other five encode transcription factors HNF4-alpha associated with MODY 1, HNF1alpha associated with MODY 3, IPF with MODY 4, HNF1-Beta with MODY 5 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 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. Conclusion: Since maximum number of variations exists in exon 5 of the said gene, hence one can initially go for exon 5 followed by other exons, while screening for pathogenic MODY 3 mutations in the responsible gene by PCR-SSCP method.