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

¹Department of Endocrinology and Diabetes, Bristol Royal Hospital for Children and University of Bristol, Upper Maudlin Street, Bristol, BS2 8AE, UK
²Institute of Biomedical and Clinical Science, Peninsula Medical School, Barrack Road, Exeter EX2 5DW, UK
³Wessex Regional Genetics Laboratory and Clinical Genetics Service, Salisbury District Hospital, Salisbury, Wiltshire, SP2 8BJ, UK and Division of Human Genetics, University of Southampton, UK
⁴University laboratory of Physiology, Parks Road, Oxford, OX1 3PT, UK

Objective: Activating mutations in the KCNJ11 and ABCC8 genes encoding the Kir6.2 and SUR1 subunits of the pancreatic KATP 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 hemi-hypertrophy, a condition classically associated with neonatal hyperinsulinaemia and hypoglycaemia, who developed neonatal diabetes aged 5 weeks.

Research Design and Methods: The KCNJ11 and ABCC8 genes and microsatellite markers on chromosome 11 were analysed 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 which encompassed the ABCC8 gene and the BWS locus.

Conclusion: 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.

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This article has been cited by other articles:

				K. Hussain, S. E. Flanagan, V. V. Smith, M. Ashworth, M. Day, A. Pierro, and S. Ellard An ABCC8 Gene Mutation and Mosaic Uniparental Isodisomy Resulting in Atypical Diffuse Congenital Hyperinsulinism Diabetes, January 1, 2008; 57(1): 259 - 263. [Abstract] [Full Text] [PDF]