الفهرس 
Maturity Onset Diabetes in the Young (MODYOnly 14 pages are availabe for public view
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Abstract
Mutations in hepatocyte nuclear factor-1alpha (HNF-1alpha) gene cause one type of maturity onset diabetes of the young (MODY) called MODY3, which is characterized by poor insulin secretion in response to glucose. Our study is focused on HNF-1alpha gene related to MODY3. The aim of the present study is to detect the mutations in the HNF-1alpha gene in the Egyptian patients for the first time, and to compare the results for Egyptian patients with those in other regions of the world.
The present work includes eight Egyptian patients diagnosed with MODY3, their ages were between 12 and 17 years old. The direct sequence analyses of the exons 6, 7, 8, 9 and 10 and promoter 1 of HNF-1alpha gene were performed. The obtained results of the sequences were aligned with the normal ones which were obtained from ”NCBI” reference sequence database with the accession number NM_000545.5.
The obtained results yield single nucleotide polymorphism (SNP), of which are the missense and silent mutations. It was observed that the maximum number of the variants was the SNP variants that were found in the promoter 1, intron 7 and intron 9. Twenty different SNPs were detected in the promoter 1 only in about 75% of all patients (6 from 8 patients). The SNP variant c.1501+7G>A was detected in intron 7 and represented about 62.5% of all patients (5 from 8 patients), while the SNP variant c.1769-24T>C was found in intron 9 in about 75% of all patients (6 from 8 patients). The two previous SNP variants detected in intron regions were recorded before in different locations all over the world.
Two missense mutations were detected in this study. The first missense mutation c.1304T>A was found in the exon 6 in about 12.5% of all patients (one from eight patients). This mutation is a novel heterogeneous missense mutation. This mutation inserts the amino acid Aspartic acid in the location of the amino acid Valine at the protein code number 435 (Val435Asp). The second missense mutation c.1460G>A was detected in the exon 7 in about 62.5% of all cases (5 from 8 patients). It inserts the amino acid Asparagine in the location of the amino acid Serine at the protein code number 487 (Ser487Asn), and this mutation was mentioned before in other places outside Egypt. The missense mutation substitutes the normal amino acid to a different one, it changes the polypeptide so it can change the function of whole protein. Therefore, the mutation can affect the gene function causing several abnormal phenotypes. Based on that, we suggested that the missense mutation is the most effective one.
Also, two silent mutations were detected in this study. The first one was c.1375C>T which was found in the exon 7 in about 62.5% of all cases (5 from 8 patients). This silent mutation alters the codon of Leucine amino acid into another codon of the same amino acid (Leu459Leu). The second silent mutation was c.1545G>A that was detected in the exon 8 in about 37.5% of all patients (5 from 8 patients). It changed the codon of Threonine amino acid into another codon of the same amino acid (Thr515Thr). The previous two silent mutations were also detected before in other populations.
An agreement is noticed between the mutations on the HNF-1alpha gene detected in our study of Egyptian patients and those of other regions in the world. Because of the exon 7 carries the different three mutations (missense, silent and SNP) that were detected in our study, we can say that this exon (7) may be responsible for the MODY3 diseases in the Egyptian population. According to these results we suggest that the mutations in the HNF-1alpha gene have an essential contribution in the appearance of MODY3 disease in the Egyptian patients who were enrolled in our study.