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Paternal Uniparental Isodisomy of Chromosome 11p15.5 within the Pancreas Causes Isolated Hyperinsulinemic Hypoglycemia

Background: Loss of function mutations in the genes encoding the pancreatic β-cell ATP-sensitive potassium (KATP) channel are identified in approximately 80% of patients with diazoxide unresponsive hyperinsulinemic hypoglycemia (HH). For a small number of patients HH can occur as part of a multisyst...

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Autores principales: Flanagan, S. E., Kapoor, R. R., Smith, V. V., Hussain, K., Ellard, Sian
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Research Foundation 2011
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3356130/
https://www.ncbi.nlm.nih.gov/pubmed/22654821
http://dx.doi.org/10.3389/fendo.2011.00066
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author Flanagan, S. E.
Kapoor, R. R.
Smith, V. V.
Hussain, K.
Ellard, Sian
author_facet Flanagan, S. E.
Kapoor, R. R.
Smith, V. V.
Hussain, K.
Ellard, Sian
author_sort Flanagan, S. E.
collection PubMed
description Background: Loss of function mutations in the genes encoding the pancreatic β-cell ATP-sensitive potassium (KATP) channel are identified in approximately 80% of patients with diazoxide unresponsive hyperinsulinemic hypoglycemia (HH). For a small number of patients HH can occur as part of a multisystem disease such as Beckwith–Wiedemann syndrome (BWS). In approximately 20% of patients, BWS results from chromosome 11 paternal uniparental disomy (UPD), which causes dysregulation of imprinted growth regulation genes at 11p15.5. There is a considerable range in the clinical features and phenotypic severity associated with BWS which is likely to be due to somatic mosaicism. The cause of HH in these patients is not known. Research Design and Methods: We undertook microsatellite analysis of 12 markers spanning chromosome 11p in two patients with severe HH and diffuse disease requiring a pancreatectomy. In both patients mutations in the K(ATP) channel genes had not been identified. Results: We identified segmental paternal UPD in DNA extracted from pancreatic tissue in both patients. UPD was not observed in DNA extracted from the patient’s leukocytes or buccal samples. In both cases the UPD encompassed the differentially methylated region at chromosome 11p15.5. Despite this neither patient had any further features of BWS. Conclusion: Paternal UPD of the chromosome 11p15.5 differentially methylated region limited to the pancreatic tissue may represent a novel cause of isolated diazoxide unresponsive HH. Loss of heterozygosity studies should therefore be considered in all patients with severe HH who have undergone pancreatic surgery when K(ATP) channel mutation(s) have not been identified.
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spelling pubmed-33561302012-05-31 Paternal Uniparental Isodisomy of Chromosome 11p15.5 within the Pancreas Causes Isolated Hyperinsulinemic Hypoglycemia Flanagan, S. E. Kapoor, R. R. Smith, V. V. Hussain, K. Ellard, Sian Front Endocrinol (Lausanne) Endocrinology Background: Loss of function mutations in the genes encoding the pancreatic β-cell ATP-sensitive potassium (KATP) channel are identified in approximately 80% of patients with diazoxide unresponsive hyperinsulinemic hypoglycemia (HH). For a small number of patients HH can occur as part of a multisystem disease such as Beckwith–Wiedemann syndrome (BWS). In approximately 20% of patients, BWS results from chromosome 11 paternal uniparental disomy (UPD), which causes dysregulation of imprinted growth regulation genes at 11p15.5. There is a considerable range in the clinical features and phenotypic severity associated with BWS which is likely to be due to somatic mosaicism. The cause of HH in these patients is not known. Research Design and Methods: We undertook microsatellite analysis of 12 markers spanning chromosome 11p in two patients with severe HH and diffuse disease requiring a pancreatectomy. In both patients mutations in the K(ATP) channel genes had not been identified. Results: We identified segmental paternal UPD in DNA extracted from pancreatic tissue in both patients. UPD was not observed in DNA extracted from the patient’s leukocytes or buccal samples. In both cases the UPD encompassed the differentially methylated region at chromosome 11p15.5. Despite this neither patient had any further features of BWS. Conclusion: Paternal UPD of the chromosome 11p15.5 differentially methylated region limited to the pancreatic tissue may represent a novel cause of isolated diazoxide unresponsive HH. Loss of heterozygosity studies should therefore be considered in all patients with severe HH who have undergone pancreatic surgery when K(ATP) channel mutation(s) have not been identified. Frontiers Research Foundation 2011-11-02 /pmc/articles/PMC3356130/ /pubmed/22654821 http://dx.doi.org/10.3389/fendo.2011.00066 Text en Copyright © 2011 Flanagan, Kapoor, Smith, Hussain and Ellard. http://www.frontiersin.org/licenseagreement This is an open-access article subject to a non-exclusive license between the authors and Frontiers Media SA, which permits use, distribution and reproduction in other forums, provided the original authors and source are credited and other Frontiers conditions are complied with.
spellingShingle Endocrinology
Flanagan, S. E.
Kapoor, R. R.
Smith, V. V.
Hussain, K.
Ellard, Sian
Paternal Uniparental Isodisomy of Chromosome 11p15.5 within the Pancreas Causes Isolated Hyperinsulinemic Hypoglycemia
title Paternal Uniparental Isodisomy of Chromosome 11p15.5 within the Pancreas Causes Isolated Hyperinsulinemic Hypoglycemia
title_full Paternal Uniparental Isodisomy of Chromosome 11p15.5 within the Pancreas Causes Isolated Hyperinsulinemic Hypoglycemia
title_fullStr Paternal Uniparental Isodisomy of Chromosome 11p15.5 within the Pancreas Causes Isolated Hyperinsulinemic Hypoglycemia
title_full_unstemmed Paternal Uniparental Isodisomy of Chromosome 11p15.5 within the Pancreas Causes Isolated Hyperinsulinemic Hypoglycemia
title_short Paternal Uniparental Isodisomy of Chromosome 11p15.5 within the Pancreas Causes Isolated Hyperinsulinemic Hypoglycemia
title_sort paternal uniparental isodisomy of chromosome 11p15.5 within the pancreas causes isolated hyperinsulinemic hypoglycemia
topic Endocrinology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3356130/
https://www.ncbi.nlm.nih.gov/pubmed/22654821
http://dx.doi.org/10.3389/fendo.2011.00066
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