Isolated pancreatic aplasia due to a hypomorphic PTF1A mutation

Jayne A L Houghton, Galvin H. Swift, Charles Shaw-Smith, Sarah E. Flanagan, Elisa De Franco, Richard Caswell, Khalid Hussain, Sarar Mohamed, Majedah Abdulrasoul, Andrew T. Hattersley, Raymond J. MacDonald, Sian Ellard

Research output: Contribution to journalArticle

9 Citations (Scopus)

Abstract

Homozygous truncating mutations in the helix-loophelix transcription factor PTF1A are a rare cause of pancreatic and cerebellar agenesis. The correlation of Ptf1α 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. Genomewide 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.

Original languageEnglish (US)
Pages (from-to)2810-2815
Number of pages6
JournalDiabetes
Volume65
Issue number9
DOIs
StatePublished - Sep 1 2016

Fingerprint

Mutation
Siblings
Exocrine Pancreatic Insufficiency
Phenotype
Missense Mutation
Mutant Proteins
Pedigree
Transcriptional Activation
Single Nucleotide Polymorphism
Transfection
Transcription Factors
Parturition
Insulin
Genes
Therapeutics

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism
  • Medicine(all)

Cite this

Houghton, J. A. L., Swift, G. H., Shaw-Smith, C., Flanagan, S. E., De Franco, E., Caswell, R., ... Ellard, S. (2016). Isolated pancreatic aplasia due to a hypomorphic PTF1A mutation. Diabetes, 65(9), 2810-2815. https://doi.org/10.2337/db15-1666

Isolated pancreatic aplasia due to a hypomorphic PTF1A mutation. / Houghton, Jayne A L; Swift, Galvin H.; Shaw-Smith, Charles; Flanagan, Sarah E.; De Franco, Elisa; Caswell, Richard; Hussain, Khalid; Mohamed, Sarar; Abdulrasoul, Majedah; Hattersley, Andrew T.; MacDonald, Raymond J.; Ellard, Sian.

In: Diabetes, Vol. 65, No. 9, 01.09.2016, p. 2810-2815.

Research output: Contribution to journalArticle

Houghton, JAL, Swift, GH, Shaw-Smith, C, Flanagan, SE, De Franco, E, Caswell, R, Hussain, K, Mohamed, S, Abdulrasoul, M, Hattersley, AT, MacDonald, RJ & Ellard, S 2016, 'Isolated pancreatic aplasia due to a hypomorphic PTF1A mutation', Diabetes, vol. 65, no. 9, pp. 2810-2815. https://doi.org/10.2337/db15-1666
Houghton JAL, Swift GH, Shaw-Smith C, Flanagan SE, De Franco E, Caswell R et al. Isolated pancreatic aplasia due to a hypomorphic PTF1A mutation. Diabetes. 2016 Sep 1;65(9):2810-2815. https://doi.org/10.2337/db15-1666
Houghton, Jayne A L ; Swift, Galvin H. ; Shaw-Smith, Charles ; Flanagan, Sarah E. ; De Franco, Elisa ; Caswell, Richard ; Hussain, Khalid ; Mohamed, Sarar ; Abdulrasoul, Majedah ; Hattersley, Andrew T. ; MacDonald, Raymond J. ; Ellard, Sian. / Isolated pancreatic aplasia due to a hypomorphic PTF1A mutation. In: Diabetes. 2016 ; Vol. 65, No. 9. pp. 2810-2815.
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