Islet-1 (Isl-1) is a unique transcription factor that binds to the enhancer region of the insulin gene. To evaluate this gene in non-insulin-dependent diabetes mellitus (NIDDM), a full-length human Isl-1 cDNA was isolated and the genomic structure was characterized. The cDNA [2,395 bp plus additional poly(A) residues] contained an open reading frame from an initiator methionine at nucleotide 240 to an opal stop codon at nucleotide 1,286 (GenBank accession number UO7559), encoding a predicted protein of 349 amino acids (39 kDa). From their ends, 23 additional clones were sequenced, revealing 15 incomplete cDNAs and 8 intron-containing partially processed precursors. As determined by Northern blotting and reverse transcriptase–polymerase chain reaction analysis, Isl-1 was most abundantly expressed as a 2.4-kb mRNA in human islets, with a restricted pattern of expression in other adult human tissues. Analysis of genomic clones revealed that Isl-1 is encoded by six exons, varying in size from 168 bp (exon 5) to 1,230 bp (exon 6). Exons 2 and 3 each encode a LIM domain, while the homeodomain is completely contained within exon 4. The sequence of the proximal promoter region, including 426 bp upstream of the 5′ -end of the cDNA, revealed two potential regulatory elements, GCCAGCCGG (–414 to –406) and GCCACAGG (–357 to – 350), each differing by one base form a homologous sequence in the insulin gene (GCCACCGG) that has been shown to be a major positive regulatory element (Boam DSW, Clark AR, Docherty L: Positive and negative regulation of the human insulin gene by multiple trans-acting factors. J Biol Chem 265:8285–8296, 1990). A search by single-strand conformational polymorphism analysis for variants in the Isl-1 gene was undertaken in NIDDM patients. Three variants were identified in the cDNA, none of which alter the predicted amino acid sequence. No variants were found in the promoter. The results of these studies thus indicate that the Isl-1 gene is not a major contributor to NIDDM susceptibility in this Northern European Caucasian population.

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