Supplementary Material for: Three Novel Pathogenic Mutations in KATP Channel Genes and Somatic Imprinting Alterations of the 11p15 Region in Pancreatic Tissue in Patients with Congenital Hyperinsulinism

<p><b><i>Background/Aims:</i></b> This study was performed to investigate the molecular pathology underlying focal and diffuse congenital hyperinsulinism (CHI). <b><i>Methods:</i></b> The <i>ABCC8</i> and <i>KCNJ11</i> 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. <b><i>Results:</i></b> The 3 patients with focal CHI harbored paternally inherited <i>ABCC8</i> or <i>KCNJ11</i> mutations. Compound heterozygous <i>ABCC8</i> mutations were identified in the patient with diffuse CHI. In the 3 patients with focal CHI, homozygous <i>ABCC8</i> or <i>KCNJ11</i> 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 <i>ABCC8</i> mutations were conserved, and imprinting patterns at 11p15 were normal. <b><i>Conclusions:</i></b> The epigenetic alteration at the 11p15 region plays a central role in developing focal CHI by paternally derived mutations of the K<sub>ATP</sub> channel and maternal allelic loss at this region. MS-MLPA and microsatellite analyses are useful to investigate the molecular etiology of CHI.</p>

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