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

Permanent neonatal diabetes caused by dominant, recessive, or compound heterozygous SUR1 mutations with opposite functional effects
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.
patients, secretion, genes, molecular sequence data, research support, drug, potassium channels, dominant, genetics, insulin, cohort, research, inwardly rectifying, receptors, diabetes, diabetes mellitus, pedigree, congenital, newborn, humans, heterozygote, atp-binding cassette transporters, infant, recessive, cohort studies, diagnosis, potassium, mutation
0002-9297
375-382
Ellard, S.
e83de653-52c7-4706-9ddf-da5047a1cef5
Flanagan, S.E.
1713096d-47b2-427d-980f-3c3450a743dd
Girard, C.A.
2a00dccd-dd72-4b2c-80ff-62f3900ed8f0
Patch, A.M.
e6811f31-4c1d-4fe8-80d7-3f82fc9875cb
Harries, L.W.
f578eb4b-21bf-4bb1-bdf5-31655828a901
Parrish, A.
4af65bf4-11a6-451a-b415-4439aeb81c51
Edghill, E.L.
8b346345-a870-4c23-9688-dd2a0f3479d9
Mackay, D.J.
588a653e-9785-4a00-be71-4e547850ee4a
Proks, P.
b7c7770d-4436-4c9e-84c8-72785328c406
Shimomura, K.H.
b0f2a494-f0c0-4d77-bd76-7fbf3fc2dd01
Carson, D.J.
16495557-b3cd-42a9-b048-75e8fdc2635b
Shield, J.P.
dcd75ce0-4f58-43d0-bc8f-3c845e287cfd
Hattersley, A.T.
c555d835-dd08-415c-be14-26940d5c582d
Ashcroft, F.M.
dfef649a-4808-4504-9d83-ecdcbae8085a
Ellard, S.
e83de653-52c7-4706-9ddf-da5047a1cef5
Flanagan, S.E.
1713096d-47b2-427d-980f-3c3450a743dd
Girard, C.A.
2a00dccd-dd72-4b2c-80ff-62f3900ed8f0
Patch, A.M.
e6811f31-4c1d-4fe8-80d7-3f82fc9875cb
Harries, L.W.
f578eb4b-21bf-4bb1-bdf5-31655828a901
Parrish, A.
4af65bf4-11a6-451a-b415-4439aeb81c51
Edghill, E.L.
8b346345-a870-4c23-9688-dd2a0f3479d9
Mackay, D.J.
588a653e-9785-4a00-be71-4e547850ee4a
Proks, P.
b7c7770d-4436-4c9e-84c8-72785328c406
Shimomura, K.H.
b0f2a494-f0c0-4d77-bd76-7fbf3fc2dd01
Carson, D.J.
16495557-b3cd-42a9-b048-75e8fdc2635b
Shield, J.P.
dcd75ce0-4f58-43d0-bc8f-3c845e287cfd
Hattersley, A.T.
c555d835-dd08-415c-be14-26940d5c582d
Ashcroft, F.M.
dfef649a-4808-4504-9d83-ecdcbae8085a

Ellard, S., Flanagan, S.E., Girard, C.A., Patch, A.M., Harries, L.W., Parrish, A., Edghill, E.L., Mackay, D.J., Proks, P., Shimomura, K.H., Carson, D.J., Shield, J.P., Hattersley, A.T. and Ashcroft, F.M. (2007) Permanent neonatal diabetes caused by dominant, recessive, or compound heterozygous SUR1 mutations with opposite functional effects. The American Journal of Human Genetics, 81 (2), 375-382. (doi:10.1086/519174).

Record type: Article

Abstract

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.

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More information

Published date: 2007
Keywords: patients, secretion, genes, molecular sequence data, research support, drug, potassium channels, dominant, genetics, insulin, cohort, research, inwardly rectifying, receptors, diabetes, diabetes mellitus, pedigree, congenital, newborn, humans, heterozygote, atp-binding cassette transporters, infant, recessive, cohort studies, diagnosis, potassium, mutation

Identifiers

Local EPrints ID: 59697
URI: http://eprints.soton.ac.uk/id/eprint/59697
ISSN: 0002-9297
PURE UUID: f85b6362-a9dc-4c22-84ff-9ad17618a3c6
ORCID for D.J. Mackay: ORCID iD orcid.org/0000-0003-3088-4401

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Date deposited: 03 Sep 2008
Last modified: 10 Dec 2019 01:50

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Contributors

Author: S. Ellard
Author: S.E. Flanagan
Author: C.A. Girard
Author: A.M. Patch
Author: L.W. Harries
Author: A. Parrish
Author: E.L. Edghill
Author: D.J. Mackay ORCID iD
Author: P. Proks
Author: K.H. Shimomura
Author: D.J. Carson
Author: J.P. Shield
Author: A.T. Hattersley
Author: F.M. Ashcroft

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