Permanent neonatal diabetes caused by dominant, recessive, or compound heterozygous SUR1 mutations with opposite functional effects

Ellard, Sian, Flanagan, Sarah E., Girard, Christophe A., Patch, Ann-Marie, Harries, Lorna W., Parrish, Andrew, Edghill, Emma L., Mackay, Deborah J. G., Proks, Peter, Shimomura, Kenju, Haberland, Holger, Carson, Dennis J., Sheild, Julian P. H., Hattersley, Andrew T. and Ashcroft, Frances M. (2007) Permanent neonatal diabetes caused by dominant, recessive, or compound heterozygous SUR1 mutations with opposite functional effects. American Journal of Human Genetics, 81 2: 375-382. doi:10.1086/519174


Author Ellard, Sian
Flanagan, Sarah E.
Girard, Christophe A.
Patch, Ann-Marie
Harries, Lorna W.
Parrish, Andrew
Edghill, Emma L.
Mackay, Deborah J. G.
Proks, Peter
Shimomura, Kenju
Haberland, Holger
Carson, Dennis J.
Sheild, Julian P. H.
Hattersley, Andrew T.
Ashcroft, Frances M.
Title Permanent neonatal diabetes caused by dominant, recessive, or compound heterozygous SUR1 mutations with opposite functional effects
Journal name American Journal of Human Genetics   Check publisher's open access policy
ISSN 0002-9297
1537-6605
Publication date 2007-08-01
Sub-type Article (original research)
DOI 10.1086/519174
Volume 81
Issue 2
Start page 375
End page 382
Total pages 8
Place of publication Cambridge, MA, United States
Publisher Cell Press
Language eng
Formatted abstract
Heterozygous activating mutations in the KCNJ11 gene encoding the pore-forming Kir6.2 subunit of the pancreatic beta cell KATP 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 KATP 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.
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status Non-UQ

Document type: Journal Article
Sub-type: Article (original research)
Collection: Institute for Molecular Bioscience - Publications
 
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Created: Thu, 05 May 2011, 22:08:34 EST by Susan Allen on behalf of Institute for Molecular Bioscience