Permanent neonatal diabetes caused by dominant, recessive, or compound heterozygous SUR1 mutations with opposite functional effects.
Heterozygous activating mutations in the KCNJ11 gene encoding the pore-forming Kir6.2 subunit of the pancreatic beta cell K(ATP) channel are the most common cause of permanent neonatal diabetes (PNDM). Patients with PNDM due to a heterozygous activating mutation in the ABCC8 gene encoding the SUR1 regulatory subunit of the K(ATP) channel have recently been reported. We studied a cohort of 59 patients with permanent diabetes who received a diagnosis before 6 mo of age and who did not have a KCNJ11 mutation. ABCC8 gene mutations were identified in 16 of 59 patients and included 8 patients with heterozygous de novo mutations. A recessive mode of inheritance was observed in eight patients with homozygous, mosaic, or compound heterozygous mutations. Functional studies of selected mutations showed a reduced response to ATP consistent with an activating mutation that results in reduced insulin secretion. A novel mutational mechanism was observed in which a heterozygous activating mutation resulted in PNDM only when a second, loss-of-function mutation was also present.
Ellard
Sian
S
Institute of Biomedical and Clinical Science, Peninsula Medical School, Exeter, EX2 5DW, and Wessex Regional Genetics Labs, Salisbury District Hospital, UK.
Flanagan
Sarah E
SE
Girard
Christophe A
CA
Patch
Ann-Marie
AM
Harries
Lorna W
LW
Parrish
Andrew
A
Edghill
Emma L
EL
Mackay
Deborah J G
DJ
Proks
Peter
P
Shimomura
Kenju
K
Haberland
Holger
H
Carson
Dennis J
DJ
Shield
Julian P H
JP
Hattersley
Andrew T
AT
Ashcroft
Frances M
FM
D018528:ATP-Binding Cassette Transporters / Q000235:genetics*; D015331:Cohort Studies; D003920:Diabetes Mellitus / Q000151:congenital* / Q000235:genetics*; D005799:Genes, Dominant; D005808:Genes, Recessive; D006579:Heterozygote; D006801:Humans; D007231:Infant, Newborn; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D008969:Molecular Sequence Data; D009154:Mutation; D010375:Pedigree; D015221:Potassium Channels / Q000235:genetics*; D024661:Potassium Channels, Inwardly Rectifying / Q000235:genetics*; D011955:Receptors, Drug / Q000235:genetics*; 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