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New ABCC8 Mutations in Relapsing Neonatal Diabetes and Clinical Features

¹ Centre National de la Recherche Scientifique, UMR8090, Institute of Biology, Pasteur Institute, Lille, France
² Faculty of Medicine, René Descartes Paris 5 University, Paris, France
³ Department of Pediatric Endocrinology, Necker Enfants Malades Hospital, Paris, France
⁴ Department of Genetic Biochemistry, Robert Debré Hospital, Paris, France
⁵ INSERM, U845, Necker Enfants Malades Hospital, Paris, France
⁶ Endocrinology and Diabetes Research Group, Hospital de Cruces, Barakaldo, Bizkaia, Spain
⁷ Genomic Medicine, Hammersmith Hospital, Imperial College, London, U.K

Address correspondence and reprint requests to Dr. Martine Vaxillaire, CNRS UMR8090 and Institute of Biology of Lille, Institut Pasteur, 1 rue du Professeur Calmette, BP 245, 59019 Lille, France. E-mail: martine.vaxillaire{at}good.ibl.fr

Abbreviations: K_ATP channel, ATP-sensitive K⁺ channel; PND, permanent neonatal diabetes; SUR1, sulfonylurea receptor 1; TMD, transmembrane domain; TND, transient neonatal diabetes

Activating mutations in the ABCC8 gene that encodes the sulfonylurea receptor 1 (SUR1) regulatory subunit of the pancreatic islet ATP-sensitive K⁺ channel (K_ATP channel) cause both permanent and transient neonatal diabetes. Recently, we have described the novel mechanism where basal Mg-nucleotide–dependent stimulatory action of SUR1 on the Kir6.2 pore is increased. In our present study, we identified six new heterozygous ABCC8 mutations, mainly in patients presenting the transient form of neonatal diabetes (six of eight), with a median duration of initial insulin therapy of 17 months (range 0.5–38.0). Most of these mutations map to key functional domains of SUR1. Whereas Kir6.2 mutations are a common cause of permanent neonatal diabetes and in a few cases associate with the DEND (developmental delay, epilepsy, and neonatal diabetes) syndrome, SUR1 mutations are more frequent in transient (52%) compared with permanent (14%) neonatal diabetes cases screened for ABCC8 in our series. Although ketoacidosis is frequent at presentation, SUR1 mutations associate mainly with transient hyperglycemia, with possible recurrence later in life. One-half of the SUR1 neonatal diabetic patients presented with de novo mutations. In some familial cases, diabetes is not always present in the adult carriers of SUR1 mutations, supporting variability in their clinical expressivity that remains to be fully explained.

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