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An ATP-Binding Mutation (G334D) in KCNJ11 Is Associated With a Sulfonylurea-Insensitive Form of Developmental Delay, Epilepsy, and Neonatal Diabetes

¹ Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, Missouri
² Department of Pediatrics, University of Chieti, Chieti, Italy
³ Bambino Gesù Children’s Hospital IRCCS, Piazza S Onofrio 4, 00164 Rome, Italy
⁴ S. Raffaele Scientific Park Foundation, Rome, Italy
⁵ Department of Internal Medicine, University of Tor Vergata, Rome, Italy

Address correspondence and reprint requests to C.G. Nichols, Department of Cell Biology and Physiology, Washington University School of Medicine, 660 South Euclid Ave., St. Louis, MO 63110. E-mail: cnichols{at}wustl.edu. Or to F. Barbetti, S. Raffaele Scientific Park Foundation, Room B303, Via di Castelromano, 100, 00128, Rome, Italy. E-mail: fabrizio.barbetti{at}spr-r.it

Abbreviations: DEND, developmental delay, epilepsy, and neonatal diabetes; K_ATP channel, ATP-sensitive K⁺ channel; NDM, neonatal diabetes mellitus; PNDM, permanent NDM

Mutations in the pancreatic ATP-sensitive K⁺ channel (K_ATP channel) cause permanent neonatal diabetes mellitus (PNDM) in humans. All of the K_ATP channel mutations examined result in decreased ATP inhibition, which in turn is predicted to suppress insulin secretion. Here we describe a patient with severe PNDM, which includes developmental delay and epilepsy, in addition to neonatal diabetes (developmental delay, epilepsy, and neonatal diabetes [DEND]), due to a G334D mutation in the Kir6.2 subunit of K_ATP channel. The patient was wholly unresponsive to sulfonylurea therapy (up to 1.14 mg · kg^–1 · day^–1) and remained insulin dependent. Consistent with the putative role of G334 as an ATP-binding residue, reconstituted homomeric and mixed WT+G334D channels exhibit absent or reduced ATP sensitivity but normal gating behavior in the absence of ATP. In disagreement with the sulfonylurea insensitivity of the affected patient, the G334D mutation has no effect on the sulfonylurea inhibition of reconstituted channels in excised patches. However, in macroscopic rubidium-efflux assays in intact cells, reconstituted mutant channels do exhibit a decreased, but still present, sulfonylurea response. The results demonstrate that ATP-binding site mutations can indeed cause DEND and suggest the possibility that sulfonylurea insensitivity of such patients may be a secondary reflection of the presence of DEND rather than a simple reflection of the underlying molecular basis.

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