The University of Southampton
University of Southampton Institutional Repository

Mosaic paternal uniparental isodisomy and an ABCC8 gene mutation in a patient with permanent neonatal diabetes and hemihypertrophy

Mosaic paternal uniparental isodisomy and an ABCC8 gene mutation in a patient with permanent neonatal diabetes and hemihypertrophy
Mosaic paternal uniparental isodisomy and an ABCC8 gene mutation in a patient with permanent neonatal diabetes and hemihypertrophy
OBJECTIVE: Activating mutations in the KCNJ11 and ABCC8 genes encoding the Kir6.2 and SUR1 subunits of the pancreatic ATP-sensitive K(+) channel are the most common cause of permanent neonatal diabetes. In contrast to KCNJ11, where only dominant heterozygous mutations have been identified, recessively acting ABCC8 mutations have recently been found in some patients with neonatal diabetes. These genes are co-located on chromosome 11p15.1, centromeric to the imprinted Beckwith-Wiedemann syndrome (BWS) locus at 11p15.5. We investigated a male with hemihypertrophy, a condition classically associated with neonatal hyperinsulinemia and hypoglycemia, who developed neonatal diabetes at age 5 weeks. RESEARCH DESIGN AND METHODS: The KCNJ11 and ABCC8 genes and microsatellite markers on chromosome 11 were analyzed in DNA samples from the patient and his parents. RESULTS: A paternally inherited activating mutation (N72S) in the ABCC8 gene was identified in the proband. The mutation was present at 70% in the patient's leukocytes and 50% in buccal cells. Microsatellite analysis demonstrated mosaic segmental paternal uniparental isodisomy (UPD) of 11pter-11p14 in the proband that encompassed the ABCC8 gene and the BWS locus. CONCLUSIONS: We report a patient with neonatal diabetes, hemihypertrophy, and relatively high birth weight resulting from telomeric segmental paternal UPD of chromosome 11, which unmasks a recessively acting gain-of-function mutation in the ABCC8 gene and causes deregulation of imprinted genes at the BWS locus on 11p15.5
methods, beckwith-wiedemann syndrome, genes, drug, receptors, kidney, infant, atp-binding cassette transporters, humans, mosaicism, potassium, hypoglycemia, weight, potassium channels, diabetes, mutation, uniparental disomy, birth, human, leukocytes, dna, male, inwardly rectifying, research, analysis, research design, microsatellite repeats, genetics, design, patients, research support, endocrinology, parents, newborn, chromosomes, birth weight, pair 11, diabetes mellitus, type 1, report, syndrome, functional laterality, pathology
0012-1797
255-258
Shield, J.P.
dcd75ce0-4f58-43d0-bc8f-3c845e287cfd
Flanagan, S.E.
1713096d-47b2-427d-980f-3c3450a743dd
Mackay, D.J.
588a653e-9785-4a00-be71-4e547850ee4a
Harries, L.W.
f578eb4b-21bf-4bb1-bdf5-31655828a901
Proks, P.
b7c7770d-4436-4c9e-84c8-72785328c406
Girard, C.
c7f0207e-6613-46fd-8246-a9c7be304df3
Ashcroft, F.M.
dfef649a-4808-4504-9d83-ecdcbae8085a
Temple, I.K.
d63e7c66-9fb0-46c8-855d-ee2607e6c226
Ellard, S.
e83de653-52c7-4706-9ddf-da5047a1cef5
Shield, J.P.
dcd75ce0-4f58-43d0-bc8f-3c845e287cfd
Flanagan, S.E.
1713096d-47b2-427d-980f-3c3450a743dd
Mackay, D.J.
588a653e-9785-4a00-be71-4e547850ee4a
Harries, L.W.
f578eb4b-21bf-4bb1-bdf5-31655828a901
Proks, P.
b7c7770d-4436-4c9e-84c8-72785328c406
Girard, C.
c7f0207e-6613-46fd-8246-a9c7be304df3
Ashcroft, F.M.
dfef649a-4808-4504-9d83-ecdcbae8085a
Temple, I.K.
d63e7c66-9fb0-46c8-855d-ee2607e6c226
Ellard, S.
e83de653-52c7-4706-9ddf-da5047a1cef5

Shield, J.P., Flanagan, S.E., Mackay, D.J., Harries, L.W., Proks, P., Girard, C., Ashcroft, F.M., Temple, I.K. and Ellard, S. (2008) Mosaic paternal uniparental isodisomy and an ABCC8 gene mutation in a patient with permanent neonatal diabetes and hemihypertrophy. Diabetes, 57 (1), 255-258. (doi:10.2337/db07-0999).

Record type: Article

Abstract

OBJECTIVE: Activating mutations in the KCNJ11 and ABCC8 genes encoding the Kir6.2 and SUR1 subunits of the pancreatic ATP-sensitive K(+) channel are the most common cause of permanent neonatal diabetes. In contrast to KCNJ11, where only dominant heterozygous mutations have been identified, recessively acting ABCC8 mutations have recently been found in some patients with neonatal diabetes. These genes are co-located on chromosome 11p15.1, centromeric to the imprinted Beckwith-Wiedemann syndrome (BWS) locus at 11p15.5. We investigated a male with hemihypertrophy, a condition classically associated with neonatal hyperinsulinemia and hypoglycemia, who developed neonatal diabetes at age 5 weeks. RESEARCH DESIGN AND METHODS: The KCNJ11 and ABCC8 genes and microsatellite markers on chromosome 11 were analyzed in DNA samples from the patient and his parents. RESULTS: A paternally inherited activating mutation (N72S) in the ABCC8 gene was identified in the proband. The mutation was present at 70% in the patient's leukocytes and 50% in buccal cells. Microsatellite analysis demonstrated mosaic segmental paternal uniparental isodisomy (UPD) of 11pter-11p14 in the proband that encompassed the ABCC8 gene and the BWS locus. CONCLUSIONS: We report a patient with neonatal diabetes, hemihypertrophy, and relatively high birth weight resulting from telomeric segmental paternal UPD of chromosome 11, which unmasks a recessively acting gain-of-function mutation in the ABCC8 gene and causes deregulation of imprinted genes at the BWS locus on 11p15.5

Full text not available from this repository.

More information

Published date: 2008
Keywords: methods, beckwith-wiedemann syndrome, genes, drug, receptors, kidney, infant, atp-binding cassette transporters, humans, mosaicism, potassium, hypoglycemia, weight, potassium channels, diabetes, mutation, uniparental disomy, birth, human, leukocytes, dna, male, inwardly rectifying, research, analysis, research design, microsatellite repeats, genetics, design, patients, research support, endocrinology, parents, newborn, chromosomes, birth weight, pair 11, diabetes mellitus, type 1, report, syndrome, functional laterality, pathology
Organisations: Medicine

Identifiers

Local EPrints ID: 60234
URI: http://eprints.soton.ac.uk/id/eprint/60234
ISSN: 0012-1797
PURE UUID: cfca5c32-9fcd-48af-89d2-73cb682f1927
ORCID for D.J. Mackay: ORCID iD orcid.org/0000-0003-3088-4401
ORCID for I.K. Temple: ORCID iD orcid.org/0000-0002-6045-1781

Catalogue record

Date deposited: 10 Sep 2008
Last modified: 03 Dec 2019 01:56

Export record

Altmetrics

Contributors

Author: J.P. Shield
Author: S.E. Flanagan
Author: D.J. Mackay ORCID iD
Author: L.W. Harries
Author: P. Proks
Author: C. Girard
Author: F.M. Ashcroft
Author: I.K. Temple ORCID iD
Author: S. Ellard

University divisions

Download statistics

Downloads from ePrints over the past year. Other digital versions may also be available to download e.g. from the publisher's website.

View more statistics

Atom RSS 1.0 RSS 2.0

Contact ePrints Soton: eprints@soton.ac.uk

ePrints Soton supports OAI 2.0 with a base URL of http://eprints.soton.ac.uk/cgi/oai2

This repository has been built using EPrints software, developed at the University of Southampton, but available to everyone to use.

We use cookies to ensure that we give you the best experience on our website. If you continue without changing your settings, we will assume that you are happy to receive cookies on the University of Southampton website.

×