Three novel pathogenic mutations in KATP channel genes and somatic imprinting alterations of the 11p15 region in pancreatic tissue in patients with congenital hyperinsulinism
This study was performed to investigate the molecular pathology underlying focal and diffuse congenital hyperinsulinism (CHI). The ABCC8 and KCNJ11 genes were analyzed in 3 patients with focal CHI and in 1 patient with diffuse CHI. Immunohistochemistry, real-time PCR, methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA) and microsatellite marker analyses of the 11p15 region were performed on both normal tissues and adenomatous hyperplasia lesions. The 3 patients with focal CHI harbored paternally inherited ABCC8 or KCNJ11 mutations. Compound heterozygous ABCC8 mutations were identified in the patient with diffuse CHI. In the 3 patients with focal CHI, homozygous ABCC8 or KCNJ11 mutations were identified within the lesions. MLPA and real-time PCR revealed the presence of two copies of 11p15. MS-MLPA and microsatellite analyses demonstrated abnormal imprinting patterns and focal loss of maternal 11p13-15 within the lesions. In contrast, parental heterozygosity was preserved in the normal tissue. In the patient with diffuse CHI, the two ABCC8 mutations were conserved, and imprinting patterns at 11p15 were normal. The epigenetic alteration at the 11p15 region plays a central role in developing focal CHI by paternally derived mutations of the KATP channel and maternal allelic loss at this region. MS-MLPA and microsatellite analyses are useful to investigate the molecular etiology of CHI.