Isolation of a cDNA Clone Encoding a K_ATP Channel–Like Protein Expressed in Insulin-Secreting Cells, Localization of the Human Gene to Chromosome Band 21q22.1, and Linkage Studies With NIDDM

Abstract

The metabolism of glucose in insulin-secreting cells leads to closure of ATP-sensitive K⁺ channels (K_ATP), an event that initiates the insulin secretory process. Defects in insulin secretion are a common feature of non-insulin-dependent diabetes mellitus (NIDDM), and the β-cell K_ATP that couples metabolism and membrane potential is a candidate for contributing to the development of this clinically and genetically heterogeneous disorder. We screened a hamster insulinoma cDNA library by low-stringency hybridization with a probe coding for the G-protein-coupled inwardly rectifying K⁺ channel GIRK1/KGA and isolated clones encoding a protein, K_ATP-2, whose sequence is 90% similar to that of the recently described K_ATP-1, an ATP-sensitive K⁺ channel expressed in heart and other tissues. RNA blotting showed that K_ATP mRNA was present in insulin-secreting cells and brain but not in heart. To assess the contribution of K_ATP-2 to the development of NIDDM, the human K_ATP-2 gene (symbol KCNJ7) was isolated and mapped to chromosome band 21q22.1 by fluorescence in situ hybridization. A simple tandem repeat DNA polymorphism, D21S1255, was identified in the region of the K_ATP-2 gene, and linkage studies between this marker and NIDDM were carried out in a group of Mexican-American sib pairs with NIDDM. There was no evidence for linkage between D21S1255 and NIDDM, indicating that K_ATP-2 is not a major susceptibility gene in this population.