Mosaic Paternal Uniparental Isodisomy and an ABCC8 Gene Mutation in a Patient With Permanent Neonatal Diabetes and Hemihypertrophy

摘要

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, reces-sively acting ABCC8 mutations have recently been found in some patients with neonatal diabetes. These genes are co-located on chromosome llp15.1, centromeric to the imprinted Beckwith-Wiedemann syndrome (BWS) locus at 11p 15.5. 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.