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Mutations in ATP-sensitive K+ channel genes cause transient neonatal diabetes and permanent diabetes in childhood or adulthood

Mutations in ATP-sensitive K+ channel genes cause transient neonatal diabetes and permanent diabetes in childhood or adulthood
Mutations in ATP-sensitive K+ channel genes cause transient neonatal diabetes and permanent diabetes in childhood or adulthood
Transient neonatal diabetes mellitus (TNDM) is diagnosed in the first 6 months of life, with remission in infancy or early childhood. For approximately 50% of patients, their diabetes will relapse in later life. The majority of cases result from anomalies of the imprinted region on chromosome 6q24, and 14 patients with ATP-sensitive K+ channel (K(ATP) channel) gene mutations have been reported. We determined the 6q24 status in 97 patients with TNDM. In patients in whom no abnormality was identified, the KCNJ11 gene and/or ABCC8 gene, which encode the Kir6.2 and SUR1 subunits of the pancreatic beta-cell K(ATP) channel, were sequenced. K(ATP) channel mutations were found in 25 of 97 (26%) TNDM probands (12 KCNJ11 and 13 ABCC8), while 69 of 97 (71%) had chromosome 6q24 abnormalities. The phenotype associated with KCNJ11 and ABCC8 mutations was similar but markedly different from 6q24 patients who had a lower birth weight and who were diagnosed and remitted earlier (all P < 0.001). K(ATP) channel mutations were identified in 26 additional family members, 17 of whom had diabetes. Of 42 diabetic patients, 91% diagnosed before 6 months remitted, but those diagnosed after 6 months had permanent diabetes (P < 0.0001). K(ATP) channel mutations account for 89% of patients with non-6q24 TNDM and result in a discrete clinical subtype that includes biphasic diabetes that can be treated with sulfonylureas. Remitting neonatal diabetes was observed in two of three mutation carriers, and permanent diabetes occurred after 6 months of age in subjects without an initial diagnosis of neonatal diabetes.
preschool, phenotype, mutation, adenosine triphosphate, drug, humans, diabetes, infant, weight, family, genetics, birth weight, receptors, patients, birth, pedigree, research support, genes, diabetes mellitus, potassium, child, atp-binding cassette transporters, childhood, adenosine, inwardly rectifying, abnormalities, potassium channels, diagnosis, research, newborn
0012-1797
1930-1937
Flanagan, Sarah E.
ad5fb709-7f4b-4063-9b9f-bdf9c1cf1d2b
Patch, Ann-Marie
eec11d53-c5de-4107-a1de-1175f7ab9583
Mackay, Deborah J.G.
588a653e-9785-4a00-be71-4e547850ee4a
Edghill, Emma L.
227f9dd9-d2f7-43e1-8795-9b6d41fa6ca7
Gloyn, Anna L.
e1ef7043-a852-4f6d-ad90-a644e328af88
Robinson, David
dcef4b3b-ac9b-4c1b-b8b2-1bee4b81a8cc
Shield, Julian P.H.
b7c65f5e-9a39-429d-8c1a-8ffd911abe71
Temple, Karen
0705afec-2eba-40b6-a60f-f5548d02eeea
Ellard, Sian
6c9b0ede-8980-4602-b063-444b165baa09
Hattersley, Andrew T.
429254b8-e75b-46bd-a6f6-274130336b0d
Flanagan, Sarah E.
ad5fb709-7f4b-4063-9b9f-bdf9c1cf1d2b
Patch, Ann-Marie
eec11d53-c5de-4107-a1de-1175f7ab9583
Mackay, Deborah J.G.
588a653e-9785-4a00-be71-4e547850ee4a
Edghill, Emma L.
227f9dd9-d2f7-43e1-8795-9b6d41fa6ca7
Gloyn, Anna L.
e1ef7043-a852-4f6d-ad90-a644e328af88
Robinson, David
dcef4b3b-ac9b-4c1b-b8b2-1bee4b81a8cc
Shield, Julian P.H.
b7c65f5e-9a39-429d-8c1a-8ffd911abe71
Temple, Karen
0705afec-2eba-40b6-a60f-f5548d02eeea
Ellard, Sian
6c9b0ede-8980-4602-b063-444b165baa09
Hattersley, Andrew T.
429254b8-e75b-46bd-a6f6-274130336b0d

Flanagan, Sarah E., Patch, Ann-Marie, Mackay, Deborah J.G., Edghill, Emma L., Gloyn, Anna L., Robinson, David, Shield, Julian P.H., Temple, Karen, Ellard, Sian and Hattersley, Andrew T. (2007) Mutations in ATP-sensitive K+ channel genes cause transient neonatal diabetes and permanent diabetes in childhood or adulthood. Diabetes, 56 (7), 1930-1937. (doi:10.2337/db07-0043).

Record type: Article

Abstract

Transient neonatal diabetes mellitus (TNDM) is diagnosed in the first 6 months of life, with remission in infancy or early childhood. For approximately 50% of patients, their diabetes will relapse in later life. The majority of cases result from anomalies of the imprinted region on chromosome 6q24, and 14 patients with ATP-sensitive K+ channel (K(ATP) channel) gene mutations have been reported. We determined the 6q24 status in 97 patients with TNDM. In patients in whom no abnormality was identified, the KCNJ11 gene and/or ABCC8 gene, which encode the Kir6.2 and SUR1 subunits of the pancreatic beta-cell K(ATP) channel, were sequenced. K(ATP) channel mutations were found in 25 of 97 (26%) TNDM probands (12 KCNJ11 and 13 ABCC8), while 69 of 97 (71%) had chromosome 6q24 abnormalities. The phenotype associated with KCNJ11 and ABCC8 mutations was similar but markedly different from 6q24 patients who had a lower birth weight and who were diagnosed and remitted earlier (all P < 0.001). K(ATP) channel mutations were identified in 26 additional family members, 17 of whom had diabetes. Of 42 diabetic patients, 91% diagnosed before 6 months remitted, but those diagnosed after 6 months had permanent diabetes (P < 0.0001). K(ATP) channel mutations account for 89% of patients with non-6q24 TNDM and result in a discrete clinical subtype that includes biphasic diabetes that can be treated with sulfonylureas. Remitting neonatal diabetes was observed in two of three mutation carriers, and permanent diabetes occurred after 6 months of age in subjects without an initial diagnosis of neonatal diabetes.

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More information

Published date: 19 April 2007
Keywords: preschool, phenotype, mutation, adenosine triphosphate, drug, humans, diabetes, infant, weight, family, genetics, birth weight, receptors, patients, birth, pedigree, research support, genes, diabetes mellitus, potassium, child, atp-binding cassette transporters, childhood, adenosine, inwardly rectifying, abnormalities, potassium channels, diagnosis, research, newborn

Identifiers

Local EPrints ID: 59729
URI: http://eprints.soton.ac.uk/id/eprint/59729
ISSN: 0012-1797
PURE UUID: 63022b61-0994-4011-a4dd-3ebb5016fa34
ORCID for Deborah J.G. Mackay: ORCID iD orcid.org/0000-0003-3088-4401

Catalogue record

Date deposited: 04 Sep 2008
Last modified: 17 Dec 2019 01:54

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