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

The metabolism of glucose in insulin-secreting cells leads to closure of ATP-sensitive K+ channels (K+), 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 beta-cell K-ATP that couples metabolism and membrane potential is a candidate fo r contributing to the development of this clinically and genetically h eterogeneous disorder. We screened a hamster insulinoma cDNA library b y low-stringency hybridization with a probe coding for the G-protein-c oupled inwardly rectifying K+ channel GIRK1/KGA and isolated clones en coding a protein, K-ATP-2, whose sequence is 90% similar to that of th e recently described K-ATP-1, an ATP-sensitive K+ channel expressed in heart and other tissues. RNA blotting showed that K-ATP mRNA was pres ent in insulin-secreting cells and brain but not in heart. To assess t he contribution of K-ATP-2 to the development of NIDDM, the human K-AT P-2 gene (symbol KCNJ7) was isolated and mapped to chromosome band 21q 22.1 by fluorescence in situ hybridization. A simple tandem repeat DNA polymorphism, D21S1255, was identified in the region of the K-ATP-2 g ene, and linkage studies between this marker and NIDDM were carried ou t in a group of Mexican-American sib pairs with NIDDM. There was no ev idence for linkage between D21S1255 and NIDDM, indicating that K-ATP-2 is not a major susceptibility gene in this population.