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.

Public Health Relevance

This translational research project represents a continuation of efforts to define the molecular causes of congenital hyperinsulinism (HI), the most common and most difficult form of hypoglycemia to diagnose and treat in infants and children. This new proposal takes advantage of new technologies developed for genome- wide association studies and high-throughput DNA sequencing to identify novel molecular defects and new sites of genetic mutation in these children. The data will provide important insight into regulation of insulin secretion in normal humans as well as a guide to improving the diagnosis and treatment of children with HI.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37DK056268-12
Application #
7872913
Study Section
Clinical and Integrative Diabetes and Obesity Study Section (CIDO)
Program Officer
Mckeon, Catherine T
Project Start
1999-08-15
Project End
2014-04-30
Budget Start
2010-05-01
Budget End
2011-04-30
Support Year
12
Fiscal Year
2010
Total Cost
$693,339
Indirect Cost
Name
Children's Hospital of Philadelphia
Department
Type
DUNS #
073757627
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Srivastava, Shekhar; Li, Zhai; Soomro, Irfana et al. (2018) Regulation of KATP Channel Trafficking in Pancreatic ?-Cells by Protein Histidine Phosphorylation. Diabetes 67:849-860
Tung, Joanna Yuet-Ling; Boodhansingh, Kara; Stanley, Charles A et al. (2018) Clinical heterogeneity of hyperinsulinism due to HNF1A and HNF4A mutations. Pediatr Diabetes 19:910-916
Gibson, Christopher E; Boodhansingh, Kara E; Li, Changhong et al. (2018) Congenital Hyperinsulinism in Infants with Turner Syndrome: Possible Association with Monosomy X and KDM6A Haploinsufficiency. Horm Res Paediatr 89:413-422
Li, Changhong; Ackermann, Amanda M; Boodhansingh, Kara E et al. (2017) Functional and Metabolomic Consequences of KATP Channel Inactivation in Human Islets. Diabetes 66:1901-1913
De Leon, Diva D; Stanley, Charles A (2017) Congenital Hypoglycemia Disorders: New Aspects of Etiology, Diagnosis, Treatment and Outcomes: Highlights of the Proceedings of the Congenital Hypoglycemia Disorders Symposium, Philadelphia April 2016. Pediatr Diabetes 18:3-9
Barrosse-Antle, Mary; Su, Chang; Chen, Pan et al. (2017) A severe case of hyperinsulinism due to hemizygous activating mutation of glutamate dehydrogenase. Pediatr Diabetes 18:911-916
Ferrara, Christine T; Boodhansingh, Kara E; Paradies, Eleonora et al. (2017) Novel Hypoglycemia Phenotype in Congenital Hyperinsulinism Due to Dominant Mutations of Uncoupling Protein 2. J Clin Endocrinol Metab 102:942-949
Kalish, Jennifer M; Boodhansingh, Kara E; Bhatti, Tricia R et al. (2016) Congenital hyperinsulinism in children with paternal 11p uniparental isodisomy and Beckwith-Wiedemann syndrome. J Med Genet 53:53-61
Stanley, Charles A (2016) Perspective on the Genetics and Diagnosis of Congenital Hyperinsulinism Disorders. J Clin Endocrinol Metab 101:815-26
Bhatti, Tricia R; Ganapathy, Karthik; Huppmann, Alison R et al. (2016) Histologic and Molecular Profile of Pediatric Insulinomas: Evidence of a Paternal Parent-of-Origin Effect. J Clin Endocrinol Metab 101:914-22

Showing the most recent 10 out of 33 publications