Partial ABCC8 gene deletion mutations causing diazoxide-unresponsive hyperinsulinaemic hypoglycaemia
| Autor: | Ritika Kapoor, Indraneel Banerjee, Sarah E. Flanagan, Dariusz Rokicki, Annet Damhuis, Khalid Hussain, Craig Jefferies, Sian Ellard |
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| Rok vydání: | 2011 |
| Předmět: |
Proband
Heterozygote Receptors Drug Endocrinology Diabetes and Metabolism Gene Dosage Mutation Missense Sulfonylurea Receptors Compound heterozygosity medicine.disease_cause Gene dosage ABCC8 Internal Medicine medicine Humans Missense mutation Multiplex ligation-dependent probe amplification Potassium Channels Inwardly Rectifying Genetic testing Genetics Mutation biology medicine.diagnostic_test business.industry Diazoxide Pedigree Pediatrics Perinatology and Child Health biology.protein ATP-Binding Cassette Transporters Congenital Hyperinsulinism business Gene Deletion |
| Zdroj: | Pediatric Diabetes. 13:285-289 |
| ISSN: | 1399-543X |
| DOI: | 10.1111/j.1399-5448.2011.00821.x |
| Popis: | Inactivating mutations in the pancreatic beta cell ATP-sensitive potassium (K(ATP) ) channel genes are identified by sequencing in approximately 80% of patients with diazoxide-unresponsive hyperinsulinaemic hypoglycaemia (HH). Genetic testing is clinically important as the mode of inheritance of a K(ATP) channel mutation(s) provides information on the histological subtype. For example in patients with a single paternally inherited mutation a focal lesion is possible and once confirmed, the patient can undergo a curative lesionectomy. By contrast, recessive inheritance indicates diffuse disease, which requires near-total pancreatectomy, if medical management is unsuccessful. We investigated ABCC8 and KCNJ11 gene dosage in 29 probands from a cohort of 125 with diazoxide-unresponsive HH where sequencing did not provide a genetic diagnosis. We identified heterozygous partial ABCC8 deletions in four probands. In two cases with focal pancreatic disease, a paternally inherited deletion was found. Two other probands with diffuse pancreatic disease were compound heterozygotes for a deletion and a recessively acting mutation that had been identified by sequencing. Family member studies confirmed compound heterozygosity for the deletion and the missense mutation in two affected siblings of one proband. Heterozygous deletions of the ABCC8 gene are a rare, but important cause of diazoxide-unresponsive HH. Dosage analysis should be undertaken in all patients when sequencing analysis does not confirm the genetic diagnosis as confirmation of the mode of inheritance can guide clinical management and will provide important information regarding recurrence risk. |
| Databáze: | OpenAIRE |
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