Islet Dysregulation in Infants with Congenital Hyperinsulinism

先天性高胰岛素血症婴儿的胰岛失调

• 批准号: 9249526
• 负责人: CHARLES ALFRED STANLEY
• 金额: $ 67.59万
• 依托单位: CHILDREN'S HOSP OF PHILADELPHIA
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-05-01 至 2019-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9249526
• 关键词: 11p; Award; Beta Cell; Binding; Binding Sites; Biological Assay; Brain Injuries; Calcium; Candidate Disease Gene; Catalogs; Child; Chromosomes, Human, Pair 11; Clinical; Clinical Research; Code; Collaborations; Complementary DNA; DNA; DNA Sequence Alteration; DNA sequencing; Defect; Diabetes Mellitus; Diagnosis; Diazoxide; Diffuse; Disease; Electrophoretic Mobility Shift Assay; Epigenetic Process; Family; Family history of; Future; Gene Mutation; Genes; Genetic; Genomic DNA; Genotype; Glucose; Goals; Human; Hyperinsulinism; Hypoglycemia; In Vitro; Infant; Inherited; Instruction; Insulin; Ions; Islet Cell; Islets of Langerhans; Lesion; Link; Lithium Chloride; Lymphocyte; Measures; Medical; Methods; Methylation; MicroRNAs; Missense Mutation; Molecular; Molecular Analysis; Molecular Genetics; Mosaicism; Mutation; Mutation Analysis; Mutation Detection; Nuclear; Operative Surgical Procedures; Pancreas; Pancreatectomy; Pathology; Pathway interactions; Patients; Persistent Hyperinsulinemia Hypoglycemia of Infancy; Phenotype; Physiological; Progress Reports; Recruitment Activity; Regulation; Reporting; Research; Research Personnel; Research Project Grants; Seizures; Series; Site; Testing; Translational Research; Turner' s Syndrome; Untranslated RNA; Validation; Work; base; clinical phenotype; exome; genetic linkage analysis; genetic pedigree; genome sequencing; high risk; improved; inhibitor/antagonist; insight; insulin secretion; insulin signaling; insulinoma; islet; new technology; next generation sequencing; novel; peripheral blood; response; transcription factor; whole genome

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 9 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. The long-term goals of the research are to identify genotype-phenotype correlations in these disorders to guide diagnosis and treatment and to uncover new forms of congenital hyperinsulinism. Aim 1 will extend and expand studies of the novel genetic locus for hyperinsulinism in the historically-important dominant HI family reported by McQuarrie in 1954. Clinical phenotyping, linkage analysis, and next-gen sequencing methods have identified HK1 as a likely candidate gene. This will be confirmed by recruitment of additional pedigrees and by functional assays. Aim 2 will extend the search for defects in novel candidate genes in our large series of children with diazoxide responsive hyperinsulinism that have no identifiable mutation. We will seek to identify either post-zygotic mutations of known loci or novel additional loci using targeted next-gen sequencing methods. Aim 3 will continue our efforts to define the mechanisms of molecular defects in children who fail to respond to diazoxide and require pancreatectomy. We will search for novel cryptic or mosaic mutations 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 functional testing of insulin release and molecular analysis of cultured islets from patients undergoing surgery to identify post-zygotic, mosaic mutations; mutations in non-coding regions, and microRNA sites; or epigenetic methylation defects. RELEVANCE (See instructions): This translational research project seeks to define the molecular causes of congenital hyperinsulinemic hypoglycemia (HI). Novel candidate genes will be sought using next-gen DNA sequencing and advanced micro-methods to study pancreatic islets from children requiring pancreatectomy. The results will improve the treatment of children with HI and provide new insight into regulation of insulin secretion in normal humans.

先天性高胰岛素血症（HI）是婴儿和儿童持续低血糖的最常见原因。患有 HI 的儿童癫痫发作和永久性脑损伤的风险很高，而且低血糖的治疗极其困难。最近的研究表明，HI 与调节 β 细胞胰岛素分泌途径的遗传缺陷有关。尽管已经发现了 9 个这样的基因座，但许多患有 HI 的儿童并没有这些基因的可识别突变。这包括三分之一需要胰腺切除术的弥漫性HI病例和一半对二氮嗪治疗有反应的病例。我们的假设是，这些儿童群体中的高胰岛素血症既涉及已知位点的新分子缺陷，也涉及先前未识别的新遗传位点。该研究的长期目标是确定这些疾病的基因型与表型相关性，以指导诊断和治疗，并发现先天性高胰岛素血症的新形式。目标 1 将扩展和扩大对 McQuarrie 于 1954 年报道的历史上重要的显性 HI 家族中高胰岛素血症的新遗传位点的研究。临床表型、连锁分析和下一代测序方法已将 HK1 确定为可能的候选基因。这将通过招募额外的谱系和功能测定来证实。目标 2 将在我们大量患有二氮嗪反应性高胰岛素血症的儿童中扩大对新候选基因缺陷的搜索，这些儿童没有可识别的突变。我们将寻求使用有针对性的下一代测序方法来识别已知基因座的合子后突变或新的额外基因座。目标 3 将继续努力确定对二氮嗪无反应且需要胰腺切除术的儿童的分子缺陷机制。我们将寻找 11p 上两个相邻基因的新隐性或嵌合突变，这些突变导致这种形式的 HI 的大多数病例：ABCC8/SUR1 和 KCNJ11/Kir6.2。这将包括胰岛素释放的功能测试以及对接受手术的患者培养的胰岛进行分子分析，以识别合子后嵌合突变；非编码区和 microRNA 位点的突变；或表观遗传甲基化缺陷。 相关性（参见说明）： 该转化研究项目旨在明确先天性高胰岛素性低血糖 (HI) 的分子原因。将使用下一代 DNA 测序和先进的微观方法来寻找新的候选基因，以研究需要胰腺切除术的儿童的胰岛。研究结果将改善患有HI的儿童的治疗，并为正常人胰岛素分泌的调节提供新的见解。