Activating mutations in the gene encoding the ATP-sensitive potassium-channel subunit Kir6.2 and permanent neonatal diabetes.
BACKGROUND
Patients with permanent neonatal diabetes usually present within the first three months of life and require insulin treatment. In most, the cause is unknown. Because ATP-sensitive potassium (K(ATP)) channels mediate glucose-stimulated insulin secretion from the pancreatic beta cells, we hypothesized that activating mutations in the gene encoding the Kir6.2 subunit of this channel (KCNJ11) cause neonatal diabetes.


METHODS
We sequenced the KCNJ11 gene in 29 patients with permanent neonatal diabetes. The insulin secretory response to intravenous glucagon, glucose, and the sulfonylurea tolbutamide was assessed in patients who had mutations in the gene.


RESULTS
Six novel, heterozygous missense mutations were identified in 10 of the 29 patients. In two patients the diabetes was familial, and in eight it arose from a spontaneous mutation. Their neonatal diabetes was characterized by ketoacidosis or marked hyperglycemia and was treated with insulin. Patients did not secrete insulin in response to glucose or glucagon but did secrete insulin in response to tolbutamide. Four of the patients also had severe developmental delay and muscle weakness; three of them also had epilepsy and mild dysmorphic features. When the most common mutation in Kir6.2 was coexpressed with sulfonylurea receptor 1 in Xenopus laevis oocytes, the ability of ATP to block mutant K(ATP) channels was greatly reduced.


CONCLUSIONS
Heterozygous activating mutations in the gene encoding Kir6.2 cause permanent neonatal diabetes and may also be associated with developmental delay, muscle weakness, and epilepsy. Identification of the genetic cause of permanent neonatal diabetes may facilitate the treatment of this disease with sulfonylureas.
Gloyn
Anna L
AL
Institute of Biomedical and Clinical Science, Peninsula Medical School, Exeter, United Kingdom.
Pearson
Ewan R
ER
Antcliff
Jennifer F
JF
Proks
Peter
P
Bruining
G Jan
GJ
Slingerland
Annabelle S
AS
Howard
Neville
N
Srinivasan
Shubha
S
Silva
José M C L
JM
Molnes
Janne
J
Edghill
Emma L
EL
Frayling
Timothy M
TM
Temple
I Karen
IK
Mackay
Deborah
D
Shield
Julian P H
JP
Sumnik
Zdenek
Z
van Rhijn
Adrian
A
Wales
Jerry K H
JK
Clark
Penelope
P
Gorman
Shaun
S
Aisenberg
Javier
J
Ellard
Sian
S
Njølstad
Pål R
PR
Ashcroft
Frances M
FM
Hattersley
Andrew T
AT
D004252:DNA Mutational Analysis; D002658:Developmental Disabilities / Q000235:genetics; D003920:Diabetes Mellitus / Q000235:genetics*; D004827:Epilepsy / Q000235:genetics; D005145:Face / Q000002:abnormalities; D005260:Female; D006579:Heterozygote; D006801:Humans; D007231:Infant, Newborn; D007515:Islets of Langerhans / Q000378:metabolism; D008297:Male; D009154:Mutation; D010375:Pedigree; D024661:Potassium Channels, Inwardly Rectifying / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D017422:Sequence Analysis, DNA
D024661:Potassium Channels, Inwardly Rectifying