Isolated Pancreatic Aplasia Due to a Hypomorphic PTF1A Mutation.

2.50
Hdl Handle:
http://hdl.handle.net/11287/620286
Title:
Isolated Pancreatic Aplasia Due to a Hypomorphic PTF1A Mutation.
Authors:
Houghton, Jayne A. L.; Swift, G. H.; Shaw-Smith, Charles; Flanagan, S. E.; de Franco, E.; Caswell, Richard C.; Hussain, K.; Mohamed, S.; Abdulrasoul, M.; Hattersley, Andrew T.; MacDonald, R. J.; Ellard, Sian ( 0000-0002-7620-5526 )
Abstract:
Homozygous truncating mutations in the helix-loop-helix transcription factor PTF1A are a rare cause of pancreatic and cerebellar agenesis. The correlation of Ptf1a dosage with pancreatic phenotype in a mouse model suggested the possibility of finding hypomorphic PTF1A mutations in patients with pancreatic agenesis or neonatal diabetes but no cerebellar phenotype. Genome-wide single nucleotide polymorphism typing in two siblings with neonatal diabetes from a consanguineous pedigree revealed a large shared homozygous region (31 Mb) spanning PTF1A Sanger sequencing of PTF1A identified a novel missense mutation, p.P191T. Testing of 259 additional patients using a targeted next-generation sequencing assay for 23 neonatal diabetes genes detected one additional proband and an affected sibling with the same homozygous mutation. All four patients were diagnosed with diabetes at birth and were treated with insulin. Two of the four patients had exocrine pancreatic insufficiency requiring replacement therapy but none of the affected individuals had neurodevelopmental delay. Transient transfection assays of the mutant protein demonstrated a 75% reduction in transactivation activity. This study shows that the functional severity of a homozygous mutation impacts the severity of clinical features found in patients.
Citation:
Isolated Pancreatic Aplasia Due to a Hypomorphic PTF1A Mutation. 2016, 65 (9):2810-5 Diabetes
Publisher:
American Diabetes Association
Journal:
Diabetes
Issue Date:
Sep-2016
URI:
http://hdl.handle.net/11287/620286
DOI:
10.2337/db15-1666
PubMed ID:
27284104
Additional Links:
http://diabetes.diabetesjournals.org/cgi/pmidlookup?view=long&pmid=27284104
Note:
This article is freely available online. Click on the Additional Link above to access the full-text.
Type:
Journal Article
Language:
en
ISSN:
1939-327X
Appears in Collections:
Diabetes/Endocrine Services; Clinical Genetics (Peninsula Genetics); Molecular Genetics; 2016 RD&E publications

Full metadata record

DC FieldValue Language
dc.contributor.authorHoughton, Jayne A. L.en
dc.contributor.authorSwift, G. H.en
dc.contributor.authorShaw-Smith, Charlesen
dc.contributor.authorFlanagan, S. E.en
dc.contributor.authorde Franco, E.en
dc.contributor.authorCaswell, Richard C.en
dc.contributor.authorHussain, K.en
dc.contributor.authorMohamed, S.en
dc.contributor.authorAbdulrasoul, M.en
dc.contributor.authorHattersley, Andrew T.en
dc.contributor.authorMacDonald, R. J.en
dc.contributor.authorEllard, Sianen
dc.date.accessioned2017-03-14T15:35:26Z-
dc.date.available2017-03-14T15:35:26Z-
dc.date.issued2016-09-
dc.identifier.citationIsolated Pancreatic Aplasia Due to a Hypomorphic PTF1A Mutation. 2016, 65 (9):2810-5 Diabetesen
dc.identifier.issn1939-327X-
dc.identifier.pmid27284104-
dc.identifier.doi10.2337/db15-1666-
dc.identifier.urihttp://hdl.handle.net/11287/620286-
dc.description.abstractHomozygous truncating mutations in the helix-loop-helix transcription factor PTF1A are a rare cause of pancreatic and cerebellar agenesis. The correlation of Ptf1a dosage with pancreatic phenotype in a mouse model suggested the possibility of finding hypomorphic PTF1A mutations in patients with pancreatic agenesis or neonatal diabetes but no cerebellar phenotype. Genome-wide single nucleotide polymorphism typing in two siblings with neonatal diabetes from a consanguineous pedigree revealed a large shared homozygous region (31 Mb) spanning PTF1A Sanger sequencing of PTF1A identified a novel missense mutation, p.P191T. Testing of 259 additional patients using a targeted next-generation sequencing assay for 23 neonatal diabetes genes detected one additional proband and an affected sibling with the same homozygous mutation. All four patients were diagnosed with diabetes at birth and were treated with insulin. Two of the four patients had exocrine pancreatic insufficiency requiring replacement therapy but none of the affected individuals had neurodevelopmental delay. Transient transfection assays of the mutant protein demonstrated a 75% reduction in transactivation activity. This study shows that the functional severity of a homozygous mutation impacts the severity of clinical features found in patients.en
dc.language.isoenen
dc.publisherAmerican Diabetes Associationen
dc.relation.urlhttp://diabetes.diabetesjournals.org/cgi/pmidlookup?view=long&pmid=27284104en
dc.rightsArchived with thanks to Diabetesen
dc.subjectWessex Classification Subject Headings::Endocrinology::Diabetesen
dc.subjectWessex Classification Subject Headings::Oncology. Pathology.::Geneticsen
dc.titleIsolated Pancreatic Aplasia Due to a Hypomorphic PTF1A Mutation.en
dc.typeJournal Articleen
dc.identifier.journalDiabetesen
dc.description.noteThis article is freely available online. Click on the Additional Link above to access the full-text.en
dc.type.versionPublisheden

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