A mutation (R826W) in nucleotide-binding domain 1 of ABCC8 reduces ATPase activity and causes transient neonatal diabetes

Heidi de Wet, Peter Proks, Mathilde Lafond, Jussi Aittoniemi, Mark S. P. Sansom, Sarah E. Flanagan, Ewan R. Pearson, Andrew T. Hattersley, Frances M. Ashcroft

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    Activating mutations in the pore-forming Kir6.2 (KCNJ11) and regulatory sulphonylurea receptor SUR1 (ABCC8) subunits of the K-ATP channel are a common cause of transient neonatal diabetes mellitus (TNDM). We identified a new TNDM mutation (R826W) in the first nucleotide-binding domain (NBD1) of SUR1. The mutation was found in a region that heterodimerizes with NBD2 to form catalytic site 2. Functional analysis showed that this mutation decreases MgATP hydrolysis by purified maltose-binding protein MBP-NBD1 fusion proteins. Inhibition of ATP hydrolysis by MgADP or BeF was not changed. The results indicate that the ATPase cycle lingers in the post-hydrolytic MgADP. P-i-bound state, which is associated with channel activation. The extent of MgADP-dependent activation of KATP channel activity was unaffected by the R826W mutation, but the time course of deactivation was slowed. Channel inhibition by MgATP was reduced, leading to an increase in resting whole-cell currents. In pancreatic beta cells, this would lead to less insulin secretion and thereby diabetes.

    Original languageEnglish
    Pages (from-to)648-654
    Number of pages7
    JournalEMBO Reports
    Issue number7
    Publication statusPublished - Jul 2008


    • SUR1
    • ABCC8
    • K-ATP channel
    • nucleotide-binding domain
    • neonatal diabetes
    • ATP hydrolysis
    • KIR6.2
    • SUR1
    • GENES
    • DIMER

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