Co-inheritance of two ABCC8 mutations causing an unresponsive congenital hyperinsulinism: Clinical and functional characterization of two novel ABCC8 mutations

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• 作者：Flavio Faletra^a ; ^{faletra@burlo.trieste.it} ; Kara Snider^b ; Show-Ling Shyng^d ; Irene Bruno^a ; Emmanouil Athanasakis^a ; Paolo Gasparini^a ; Carlo Dionisi-Vici^c ; Alessandro Ventura^a ; Qing Zhou^d ; Charles A. Stanley^b ; Alberto Burlina^e
• 关键词：CHI ; congenital hyperinsulinism ; KATP ; ATP-sensitive K(+) ; SUR1 ; sulfonylurea receptor ; Kir6.2 ; inwardly rectifying potassium channel
• 刊名：Gene
• 出版年：2013
• 出版时间：1 March, 2013
• 年：2013
• 卷：516
• 期：1
• 页码：122-125
• 全文大小：320 K

文摘

Congenital hyperinsulinism (CHI) occurs as a consequence of unregulated insulin secretion from the pancreatic beta-cells. Severe recessive mutations and milder dominant mutations have been described in the ABCC8 and KCNJ11 genes encoding SUR1 and Kir6.2 subunits of the beta-cell ATP-sensitive K(+) channel. Here we report two patients with CHI unresponsive to medical therapy with diazoxide. Sequencing analysis identified a compound heterozygous mutation in ABCC8 in both patients. The first one is a carrier for the known mild dominant mutation p.Glu1506Lys jointly with the novel mutation p.Glu1323Lys. The second carries the p.Glu1323Lys mutation and a second novel mutation, p.Met1394Arg. Functional studies of both novel alleles showed reduced or null cell surface expression, typical of recessive mutations. Compound heterozygous mutations in congenital hyperinsulinism result in complex interactions. Studying these mechanisms can improve the knowledge of this disease and modify its therapy.