High Incidence of Heterozygous ABCC8 and HNF1A Mutations in Czech Patients With Congenital Hyperinsulinism
Language English Country United States Media print-electronic
Document type Journal Article, Research Support, Non-U.S. Gov't
PubMed
26431509
DOI
10.1210/jc.2015-2763
Knihovny.cz E-resources
- MeSH
- Transcriptional Activation MeSH
- DNA genetics MeSH
- Adult MeSH
- Potassium Channels, Inwardly Rectifying genetics MeSH
- Genetic Variation MeSH
- Hepatocyte Nuclear Factor 1-alpha genetics MeSH
- Hepatocyte Nuclear Factor 4 genetics MeSH
- Germinal Center Kinases MeSH
- Cohort Studies MeSH
- Infant MeSH
- Humans MeSH
- Mutation genetics MeSH
- Infant, Newborn MeSH
- Child, Preschool MeSH
- Protein Serine-Threonine Kinases genetics MeSH
- Rubidium Radioisotopes MeSH
- Sulfonylurea Receptors genetics MeSH
- Pedigree MeSH
- Pregnancy MeSH
- Congenital Hyperinsulinism epidemiology genetics MeSH
- Check Tag
- Adult MeSH
- Infant MeSH
- Humans MeSH
- Male MeSH
- Infant, Newborn MeSH
- Child, Preschool MeSH
- Pregnancy MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Geographicals
- Czech Republic epidemiology MeSH
- Names of Substances
- ABCC8 protein, human MeSH Browser
- DNA MeSH
- Potassium Channels, Inwardly Rectifying MeSH
- Hepatocyte Nuclear Factor 1-alpha MeSH
- Hepatocyte Nuclear Factor 4 MeSH
- HNF1A protein, human MeSH Browser
- HNF4A protein, human MeSH Browser
- Germinal Center Kinases MeSH
- Kir6.2 channel MeSH Browser
- Protein Serine-Threonine Kinases MeSH
- Rubidium Radioisotopes MeSH
- Sulfonylurea Receptors MeSH
CONTEXT: Congenital hyperinsulinism of infancy (CHI) represents a group of heterogeneous disorders characterized by oversecretion of insulin from pancreatic β-cells causing severe hypoglycemia. OBJECTIVE: We studied the distribution of genetic causes of CHI in a Czech population. METHODS: Countrywide collection of patients with CHI included 40 subjects (12 females, median age of diagnosis, 1 wk [interquartile range, 1-612 wk]). We sequenced the ABCC8, KCNJ11, GLUD1, GCK, HADH, UCP2, SLC16A1, HNF4A, and HNF1A genes and investigated structural changes in the ABCC8 gene. We functionally tested novel variants in the ABCC8 gene by Rb(86+) efflux assay and novel variants in the HNF1A gene by transcriptional activation and DNA-binding tests. RESULTS: We found causal mutations in 20 subjects (50%): 19 carried a heterozygous mutation while one patient was homozygous for mutation in the ABCC8 gene. Specifically, we detected 11 mutations (seven novel) in ABCC8, one novel mutation in KCNJ11, five mutations (two novel) in HNF1A, two novel mutations in HNF4A, and one in GCK. We showed a decrease of activation by diazoxide in mutant KATP channels with novel ABCC8 variants by 41-91% (median, 82%) compared with wild-type (WT) channels and reduced transcriptional activity of mutant HNF1A proteins (2.9% for p.Asn62Lysfs93* and 22% for p.Leu254Gln) accompanied by no DNA-binding ability compared with WT HNF1A. CONCLUSION: We detected a higher proportion of heterozygous mutations causing CHI compared with other cohorts probably due to lack of consanguinity and inclusion of milder CHI forms. Interestingly, HNF1A gene mutations represented the second most frequent genetic cause of CHI in the Czech Republic. Based on our results we present a genetic testing strategy specific for similar populations.
References provided by Crossref.org
Neonatal hypoglycaemia in the offsprings of parents with maturity-onset diabetes of the young (MODY)
