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A mutation in the TMD0-L0 region of SUR1 (L225P) causes Permanent Neonatal Diabetes Mellitus (PNDM)

¹Department of Cell Biology and Physiology, Washington University School of Medicine, 660 South Euclid Avenue, St. Louis, Missouri 63110
²Division of Endocrinology, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104

Correspondence: cnichols{at}wustl.edu

Key Words: Neonatal Diabetes • K_ATP • SUR1 • sulfonylurea

Objective. To examine the molecular mechanisms underlying Persistent Neonatal Diabetes Mellitus (PNDM) in a patient with a heterozygous de novo L225P mutation in the L0 region of the sulfonylurea receptor (SUR1), the regulatory subunit of the pancreatic ATP-sensitive K⁺ (K_ATP) channel.

Research Design and Methods. The effects of L225P on the properties of recombinant K_ATP channels in transfected COS cells were assessed by patch-clamp experiments on excised membrane patches and by macroscopic Rb-flux experiments in intact cells.

Results. L225P-containing K_ATP channels were significantly more active in the intact cell than WT channels. In excised membrane patches, L225P increased channel sensitivity to stimulatory Mg-nucleotides without altering intrinsic gating or channel inhibition by ATP in the absence of Mg²⁺. The effects of L225P were abolished by SUR1 mutations that prevent nucleotide hydrolysis at the Nucleotide Binding Folds. L225P did not alter channel inhibition by sulfonylurea drugs, and, consistent with this, the patient responded to treatment with oral sulfonylureas.

Conclusions. L225P underlies K_ATP channel overactivity and PNDM by specifically increasing Mg-nucleotide stimulation of the channel, consistent with recent reports of mechanistically similar PNDM-causing mutations in SUR1. The mutation does not affect sulfonylurea sensitivity and the patient is successfully treated with sulfonylureas.

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