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Islet Dysregulation in Infants with Congenital Hyperinsulinism

先天性高胰岛素血症婴儿的胰岛失调

基本信息

批准号：
8461533
负责人：
CHARLES ALFRED STANLEY
金额：
$ 61.96万
依托单位：
CHILDREN'S HOSP OF PHILADELPHIA
依托单位国家：
美国
项目类别：
财政年份：
1999
资助国家：
美国
起止时间：
1999-08-15 至 2014-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8461533
关键词：
10q 10q21 11p 3&apos Untranslated Regions Address Affect Affinity American Beta Cell Blood Cells Brain Injuries Candidate Disease Gene Child Childhood Chromosomes Clinical Research Code DNA DNA Sequence Data Defect Diagnosis Diazoxide Diffuse Disease Enzymes Epigenetic Process Family Family member Gene Mutation Genes Genetic Genomics Genotype Glucose Goals Histologic Human Hyperinsulinism Hypoglycemia Infant Insulin MCT-1 gene Maps Medical Methods Methylation MicroRNAs Molecular Mutation Mutation Analysis Operative Surgical Procedures Pancreas Pancreatectomy Pathway interactions Persistent Hyperinsulinemia Hypoglycemia of Infancy Phenotype Potassium Channel Promoter Regions Regulation Reporting Research Project Grants Seizures Site Societies TCF7L2 gene Testing Tissues Translational Research Work base design disease-causing mutation genetic linkage analysis genome wide association study hexokinase high risk improved insight insulin secretion interest islet new technology novel peripheral blood response screening

项目摘要

Project Summary Congenital hyperinsulinism (HI) is the most frequent cause of persistent hypoglycemia in infants and children. Children with HI are at high risk of seizures and permanent brain damage and treatment of their hypoglycemia is extremely difficult. Recent work has shown that HI is associated with genetic defects in the pathways regulating beta-cell insulin secretion. Although 6 such loci have been found, many children with HI have no identifiable mutation of these genes. This includes one-third of diffuse HI cases that require pancreatectomy and half of cases that are responsive to medical treatment with diazoxide. Our hypothesis is that hyperinsulinism in these groups of children involves both novel molecular defects of known loci, as well as, previously unrecognized new genetic loci. Our long-term goal is to identify genotype-phenotype correlations in these disorders to guide diagnosis and treatment and to uncover new forms of congenital hyperinsulinism. Aim 1 will identify the novel genetic locus in the historically-important dominant HI family reported by McQuarrie in 1954. Preliminary data have mapped this form of HI to an 8.4 mb region on chromosome 10q that includes the high affinity hexokinase enzyme, HK1. The phenotype of islet dysregulation in affected family members will be defined by clinical studies of insulin secretion. Linkage analysis and newly-available gene capture and high- throughput sequencing methods will be used to identify the disease-causing mutation responsible for this novel form of HI. Aim 2 will search for defects in novel candidate genes in our large group of children with diazoxide- responsive hyperinsulinism that have no identifiable mutation. Mutation analysis of peripheral blood genomic DNA will be used to examine potential candidate genes, including the novel gene on 10q that will be identified in Aim 1, HADH/SCHAD, SLC16A1/MCT-1, TCF1/HNF1, TCF4/HNF4, SIR2L4/SIRT4, and others. Aim 3 will define the mechanisms of molecular defects in children who fail to respond to diazoxide and require pancreatectomy. We will search for novel molecular defects of the two adjacent genes on 11p that are responsible for most cases of this form of HI: ABCC8/SUR1 and KCNJ11/Kir6.2. This will include mutation analysis of the entire 120 kb region of these genes using high-throughput sequencing; analyzing pancreatic tissue for genetic and histological evidence of post-zygotic, mosaic mutations; testing for mutations in promoter regions, 3'UTR regions, and microRNA sites; and screening for epigenetic methylation defects.

项目总结