Multiple ABCC8 Loss-of-Function Mutations Associated with Paradoxical Maturity-Onset Diabetes of the Young

The effects of 16 ABCC8 variants, previously reported in heterozygous association with maturity-onset diabetes of the young (MODY), some with prior diagnosis of hypersinulinism, were assessed in recombinant Kir6.2/SUR1 KATP channels. Thirteen of 16 variants cause loss-of-function, 3 of 16 have no effect on channel activity, and none causes channel gain of function. In conclusion, KATP loss of function is associated with later-onset diabetes. Any presumption that MODY-associated ABCC8 variants must induce KATP (gain of function) and that KATP inhibitors are appropriate treatment is therefore inaccurate.