HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: db07-0998v1 57/1/259    most recent Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Hussain, K. Articles by Ellard, S. Search for Related Content PubMed PubMed Citation Articles by Hussain, K. Articles by Ellard, S. Social Bookmarking                What's this?

An ABCC8 Gene Mutation and Mosaic Uniparental Isodisomy Resulting in Atypical Diffuse Congenital Hyperinsulinism

¹ Department of Endocrinology, Great Ormond Street Hospital for Children NHS Trust and the Institute of Child Health, University College London, London, U.K
² Institute of Biomedical and Clinical Science, Peninsula Medical School, Exeter, U.K
³ Department of Histology, Great Ormond Street Hospital for Children NHS Trust and the Institute of Child Health, University College London, London, U.K
⁴ Department of Molecular Genetics, Royal Devon & Exeter NHS Foundation Trust, Exeter, U.K
⁵ Department of Surgery, Great Ormond Street Hospital for Children NHS Trust and the Institute of Child Health, University College London, London, U.K

Address correspondence and reprint requests to Professor Sian Ellard, Peninsula Medical School, Barrack Road, Exeter, EX2 5DW. E-mail: sian.ellard{at}rdeft.nhs.uk

Key Words: BWS, Beckwith-Wiedemann syndrome • CHI, congenital hyperinsulinism • K_ATP channel, ATP-sensitive K⁺ channel • MLPA, multiplex ligation-dependent probe amplification • UPD, uniparental isodisomy

OBJECTIVE— Congenital hyperinsulinism (CHI) may be due to diffuse or focal pancreatic disease. The diffuse form is associated with an increase in the size of β-cell nuclei throughout the whole of the pancreas and most commonly results from recessive ATP-sensitive K⁺ channel (K_ATP channel) mutations. Focal lesions are the consequence of somatic uniparental disomy for a paternally inherited K_ATP channel mutation with enlargement of the β-cell nuclei confined to the focal lesion. Some "atypical" cases defy classification and show pancreatic β-cell nuclear enlargement confined to discrete regions of the pancreas. We investigated an atypical case with normal morphology within the tail of the pancreas but occasional enlarged endocrine nuclei in parts of the body and head.

RESEARCH DESIGN AND METHODS— The KCNJ11 and ABCC8 genes encoding the K_ATP channel subunits and microsatellite markers on chromosome 11 were analyzed in DNA samples from the patient and her parents.

RESULTS— A mosaic ABCC8 nonsense mutation (Q54X) was identified in the proband. The paternally inherited mutation was present at 90% in lymphocytes and 50% in normal pancreatic sections but between 64 and 74% in abnormal sections. Microsatellite analysis showed mosaic interstitial paternal uniparental isodisomy (UPD) for chromosome 11p15.1.

CONCLUSIONS— We report a novel genetic mechanism to explain atypical histological diffuse forms of CHI due to mosaic UPD in patients with dominantly inherited ABCC8 (or KCNJ11) gene mutations.

CiteULike    Del.icio.us    Digg    Reddit    Technorati    What's this?