Permanent Neonatal Diabetes Caused by Dominant, Recessive, or Compound Heterozygous SUR1 Mutations with Opposite Functional Effects

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• 作者：Sian Ellard ; Sarah E. Flanagan ; Christophe A. Girard ; Ann-Marie Patch ; Lorna W. Harries ; Andrew Parrish ; Emma L. Edghill ; Deborah J.G. Mackay ; Peter Proks ; Kenju Shimomura ; Holger Haberl ; Dennis J. Carson ; Julian P.H. Shield ; Andrew T. Hattersley ; Frances M. Ashcroft
• 刊名：The American Journal of Human Genetics
• 出版年：2007
• 出版时间：August 2007
• 年：2007
• 卷：81
• 期：2
• 页码：375-382
• 全文大小：561 K

文摘

Heterozygous activating mutations in the KCNJ11 gene encoding the pore-forming Kir6.2 subunit of the pancreatic beta cell K_ATP channel are the most common cause of permanent neonatal diabetes (PNDM). Patients with PNDM due to a heterozygous activating mutation in the ABCC8 gene encoding the SUR1 regulatory subunit of the K_ATP channel have recently been reported. We studied a cohort of 59 patients with permanent diabetes who received a diagnosis before 6 mo of age and who did not have a KCNJ11 mutation. ABCC8 gene mutations were identified in 16 of 59 patients and included 8 patients with heterozygous de novo mutations. A recessive mode of inheritance was observed in eight patients with homozygous, mosaic, or compound heterozygous mutations. Functional studies of selected mutations showed a reduced response to ATP consistent with an activating mutation that results in reduced insulin secretion. A novel mutational mechanism was observed in which a heterozygous activating mutation resulted in PNDM only when a second, loss-of-function mutation was also present.