Activating Mutations in Kir6.2 and Neonatal Diabetes

New Clinical Syndromes, New Scientific Insights, and New Therapy

Andrew T. Hattersley; Frances M. Ashcroft


Diabetes. 2005;54(9):2503-2513. 

In This Article


Kir6.2 mutations are associated with a range of phenotypes from transient neonatal diabetes to full DEND syndrome. The mutations show a strong genotype-phenotype relationship, and the disease phenotype is correlated with the extent of reduction in KATP channel ATP sensitivity and thus with the magnitude of the whole-cell KATP current. Mutations that cause a large reduction in ATP sensitivity will impair electrical activity in multiple tissues, whereas those that cause less reduction in ATP sensitivity will produce a smaller increase in the resting KATP current and result in neonatal diabetes alone (Fig. 3). The discovery that Kir6.2 mutations cause neonatal diabetes has resulted in a major change in treatment, with most patients being able to improve their glycemic control when insulin injections are replaced with high-dose sulfonylurea tablets. Although considerable prior knowledge of the structure and function of Kir6.2 existed, the finding of naturally occurring mutations has also offered new scientific insights; thus, it has confirmed the location of the ATP-binding site and identified new domains associated with channel gating (I296L, ref. [50]) or SUR1 interactions (F333, ref. [60]). These recent studies therefore reinforce and extend our previous understanding of the structure and function of the Kir6.2 subunit of the KATP channel and offer a novel therapeutic option to patients who previously faced life-long insulin injections.

Relationships between phenotype, genotype, and functional severity of Kir6.2 mutations and polymorphisms. Graphic indicating how the clinical severity of the disease is associated with specific mutations and how this may reflect the extent of reduction in the ATP-sensitivity of the mutated KATP channel. i-DEND, intermediate DEND syndrome; MODY, maturity-onset diabetes of the young (includes childhood and early adult onset diabetes); PNDM, permanent neonatal diabetes; TNDM, transient neonatal diabetes.


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