SEQUENCE VARIATIONS IN THE HUMAN KIR6.2 GENE, A SUBUNIT OF THE BETA-CELL ATP-SENSITIVE K-CHANNEL - NO ASSOCIATION WITH NIDDM IN WHITE CAUCASIAN SUBJECTS OR EVIDENCE OF ABNORMAL FUNCTION WHEN EXPRESSED IN-VITRO

The ATP-sensitive K-channel plays a central role in insulin release fr om pancreatic beta cells. This channel consists of two subunits: a sul phonylurea receptor, SUR1, and an inwardly rectifying K-channel subuni t, Kir6.2, We screened 135 white Caucasian patients with non-insulin-d ependent diabetes mellitus (NIDDM) and 90 non-diabetic subjects for mu tations in the Kir6.2 gene by single-stranded conformational polymorph ism (SSCP) analysis. We identified one silent mutation (A190A) and fou r missense mutations (E23K, L270V, I337V and S385C) in normal and diab etic individuals. In a single diabetic subject, we identified a two-am ino acid insertion (380KP). We also screened 39 Afro-Caribbean diabeti c subjects and identified one additional missense (L355P) and one more silent (S363S) mutation, The E23K and I337V variants were completely linked. The common variants (E23K, I337V and L270V) were found with si milar frequency in diabetic and normal subjects. Diabetic subjects wit h the variants responded normally to sulphonylurea therapy. When mutan t Kir6.2 subunits were coexpressed with SUR1 in Xenopus oocytes, there was no difference in the sensitivity of the whole-cell currents to me tabolic inhibition or to the sulphonylurea tolbutamide. We therefore c onclude that mutations in Kir6.2 are unlikely to be a major cause of N IDDM.