1. Identification of two novel frameshift mutations in the KCNJ11 gene in two Italian patients affected by Congenital Hyperinsulinism of Infancy
- Author
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Maddalena Bove, Valeria Cerioni, Luca Albarello, Stefano Mora, Ida Biunno, L. Bosio, Paola Sogno Valin, Claudio Doglioni, Laura Biagiotti, Stefano Grassi, Fabio Gervasi, Maria Carla Proverbio, Ermanna Rovida, Giuseppe Chiumello, and I. Zamproni
- Subjects
endocrine system ,Clinical Biochemistry ,Population ,Molecular Sequence Data ,Gene mutation ,ABCC8 ,Pathology and Forensic Medicine ,Frameshift mutation ,Germline mutation ,medicine ,Missense mutation ,Humans ,Genetic Predisposition to Disease ,Potassium Channels, Inwardly Rectifying ,education ,Molecular Biology ,Genetics ,education.field_of_study ,biology ,Base Sequence ,Infant, Newborn ,Infant ,medicine.disease ,Italy ,Child, Preschool ,Mutation ,biology.protein ,Congenital hyperinsulinism ,Sulfonylurea receptor ,Congenital Hyperinsulinism ,Sequence Alignment - Abstract
Congenital Hyperinsulinism of Infancy (CHI) is a genetically heterogeneous disorder characterized by profound hypoglycemia related to inappropriate insulin secretion. Two histopathologically and genetically distinct groups are recognized among patients with CHI due to ATP-sensitive potassium channel (KATP) defects: a diffuse type (Di-CHI), which involves the whole pancreas, and a focal form (Fo-CHI), which shows adenomatous islet-cell hyperplasia of a particular area within the normal pancreas. The beta-cell KATP channel consists of two essential subunits: Kir6.2 encoded by the KCNJ11 gene which is the pore-forming unit and belongs to the inwardly rectifying potassium channel family, and SUR1 (sulfonylurea receptor 1) encoded by the ABCC8 gene, which belongs to the ATP-binding cassette (ABC) transporter family. The KATP channel is an octameric complex of four Kir6.2 and four SUR1 subunits. More than one hundred mutations have been found in KATP channel genes ABCC8 and KCNJ11 , but to date only twenty mutations have been identified in KCNJ11 , most of them are missense mutations and only one is a single base deletion. The Fo-CHI has been demonstrated to arise in individuals who have a germline mutation in the paternal allele of ABCC8 or KCNJ11 in addition to a somatic loss of the maternally derived chromosome region 11p15 in adenomatous pancreatic β-cells, while Di-CHI predominantly arises from the autosomal recessive inheritance of KATP channel gene mutations. Here we describe the molecular findings in nine children who presented, in the neonatal period, with signs and symptoms of hypoglycemia and diagnosed affected by CHI according to international diagnostic criteria. Direct sequencing of the complete coding exon and promoter region of KCNJ11 gene showed, in two Italian patients, two new heterozygous mutations which result in the appearance of premature translation termination codons resulting in the premature end of Kir6.2. Interestingly most of the CHI mutations detected in other population studies are situated in the ABCC8 gene.
- Published
- 2007
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