A mutation in the TMD0-L0 region of sulfonylurea receptor-1 (L225P) causes permanent neonatal diabetes mellitus (PNDM)

Ricard Masia, Diva D. De Leon, Courtney MacMullen, Heather McKnight, Charles A. Stanley, Colin G. Nichols

Research output: Contribution to journalArticlepeer-review

35 Scopus citations

Abstract

OBJECTIVE - We sought to examine the molecular mechanisms underlying permanenent neonatal diabetes mellitus (PNDM) in a patient with a heterozygous de novo L225P mutation in the L0 region of the sulfonylurea receptor (SUR)1, the regulatory subunit of the pancreatic ATP-sensitive K+ channel (KATP channel). RESEARCH DESIGN AND METHODS - The effects of L225P on the properties of recombinant KATP 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 KATP channels were significantly more active in the intact cell than in wild-type 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 KATP 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.

Original languageEnglish
Pages (from-to)1357-1362
Number of pages6
JournalDiabetes
Volume56
Issue number5
DOIs
StatePublished - May 2007

Fingerprint

Dive into the research topics of 'A mutation in the TMD0-L0 region of sulfonylurea receptor-1 (L225P) causes permanent neonatal diabetes mellitus (PNDM)'. Together they form a unique fingerprint.

Cite this