New ABCC8 mutations in relapsing neonatal diabetes and clinical features.
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.
Vaxillaire
Martine
M
Centre National de la Recherche Scientifique, UMR8090, Institute of Biology, Pasteur Institute, Lille, France. martine.vaxillaire@good.ibl.fr
Dechaume
Aurélie
A
Busiah
Kanetee
K
Cavé
Hélène
H
Pereira
Sabrina
S
Scharfmann
Raphael
R
de Nanclares
Guiomar Perez
GP
Castano
Luis
L
Froguel
Philippe
P
Polak
Michel
M
D018528:ATP-Binding Cassette Transporters / Q000235:genetics*; D003922:Diabetes Mellitus, Type 1 / Q000188:drug therapy / Q000235:genetics*; D005260:Female; D006580:Genetic Carrier Screening; D006801:Humans; D007231:Infant, Newborn; D007328:Insulin / Q000627:therapeutic use; D008297:Male; D009154:Mutation; D015221:Potassium Channels / Q000235:genetics*; D024661:Potassium Channels, Inwardly Rectifying / Q000235:genetics*; D011955:Receptors, Drug / Q000235:genetics*; D012008:Recurrence; D064233:Sulfonylurea Receptors
C577507:ABCC8 protein, human; D018528:ATP-Binding Cassette Transporters; D007328:Insulin; D015221:Potassium Channels; D024661:Potassium Channels, Inwardly Rectifying; D011955:Receptors, Drug; D064233:Sulfonylurea Receptors