A Mutation in the TMD0-L0 Region of Sulfonylurea Receptor-1 (L225P) Causes Permanent Neonatal Diabetes Mellitus (PNDM)

• Published in: Diabetes (New York, N.Y.) Vol. 56; no. 5; pp. 1357 - 1362
• Main Authors: MASIA, Ricard, DE LEON, Diva D, MACMULLEN, Courtney, MCKNIGHT, Heather, STANLEY, Charles A, NICHOLS, Colin G
• Format: Journal Article
• Language: English
• Published: Alexandria, VA American Diabetes Association 01.05.2007
• Subjects: Amino Acid Substitution; Animals; ATP-Binding Cassette Transporters - genetics; ATP-Binding Cassette Transporters - physiology; Biological and medical sciences; Cercopithecus aethiops; COS Cells; Diabetes Mellitus, Type 1 - genetics; Diabetes Mellitus, Type 1 - physiopathology; Diabetes. Impaired glucose tolerance; Electrophysiology; Endocrine pancreas. Apud cells (diseases); Endocrinopathies; Etiopathogenesis. Screening. Investigations. Target tissue resistance; Exons; Female; Humans; Infant; Male; Medical sciences; Polymorphism, Single Nucleotide; Potassium Channels - genetics; Potassium Channels - physiology; Potassium Channels, Inwardly Rectifying - genetics; Potassium Channels, Inwardly Rectifying - physiology; Receptors, Drug - genetics; Receptors, Drug - physiology; Sulfonylurea Receptors; Transfection; Endocrinopathy; Mutation; Diabetes mellitus; Sulfonylureas; Biological receptor
• ISSN: 0012-1797; 1939-327X
• DOI: 10.2337/db06-1746

A Mutation in the TMD0-L0 Region of Sulfonylurea Receptor-1 (L225P) Causes Permanent Neonatal Diabetes Mellitus (PNDM) Ricard Masia 1 , Diva D. De Leon 2 , Courtney MacMullen 2 , Heather McKnight 2 , Charles A. Stanley 2 and Colin G. Nichols 1 1 Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, Missouri 2 Division of Endocrinology, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania Address correspondence and reprint requests to Colin 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 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 (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 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 Mg 2+ . 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. ABC, ATP-binding cassette KATP channel, ATP-sensitive K+ channel NDM, neonatal diabetes mellitus PNDM, permanenent neonatal diabetes mellitus SUR, sulfonylurea receptor TMD, transmembrane domain Footnotes Published ahead of print at http://diabetes.diabetesjournals.org on 2 February 2007. DOI: 10.2337/db06-1746. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. Accepted February 8, 2007. Received December 15, 2006. DIABETES