Skip to main content

Thank you for visiting You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Mutations in PTF1A cause pancreatic and cerebellar agenesis


Individuals with permanent neonatal diabetes mellitus usually present within the first three months of life and require insulin treatment1,2. We recently identified a locus on chromosome 10p13–p12.1 involved in permanent neonatal diabetes mellitus associated with pancreatic and cerebellar agenesis in a genome-wide linkage search of a consanguineous Pakistani family3. Here we report the further linkage analysis of this family and a second family of Northern European descent segregating an identical phenotype. Positional cloning identified the mutations 705insG and C886T in the gene PTF1A, encoding pancreas transcription factor 1α, as disease-causing sequence changes. Both mutations cause truncation of the expressed PTF1A protein C-terminal to the basic-helix-loop-helix domain. Reporter-gene studies using a minimal PTF1A deletion mutant indicate that the deleted region defines a new domain that is crucial for the function of this protein. PTF1A is known to have a role in mammalian pancreatic development4,5, and the clinical phenotype of the affected individuals implicated the protein as a key regulator of cerebellar neurogenesis. The essential role of PTF1A in normal cerebellar development was confirmed by detailed neuropathological analysis of Ptf1a−/− mice.

This is a preview of subscription content, access via your institution

Access options

Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Figure 1: Pedigrees showing microsatellite marker genotypes in the linked region on chromosome 10p13–p12.1 (a,b).
Figure 2: Identification of mutations in PTF1A as the cause of autosomal recessively inherited PNDM.
Figure 3: Transcriptional effects of deletion of the C-terminal 32 amino acids of PTF1A.
Figure 4: Cerebellar development is abnormal in the Ptf1a-deficient mouse.

Accession codes




  1. Gentz, J.C. & Cornblath, M. Transient diabetes of the newborn. Adv. Pediatr. 16, 345–363 (1969).

    CAS  PubMed  Google Scholar 

  2. Shield, J.P.H. et al. Neonatal diabetes: A study of its aetiopathology and genetic basis. Arch. Dis. Child Fetal Neonatal Ed. 76, F39–F42 (1997).

    Article  CAS  Google Scholar 

  3. Sellick, G.S., Garrett, C. & Houlston, R.S. A novel gene for neonatal diabetes mellitus maps to chromosome 10p12.1-p13. Diabetes 52, 2636–2638 (2003).

    Article  CAS  Google Scholar 

  4. Krapp, A. et al. The bHLH protein PTF1-p48 is essential for the formation of the exocrine and the correct spatial organization of the endocrine pancreas. Genes Dev. 12, 3752–3763 (1998).

    Article  CAS  Google Scholar 

  5. Kawaguchi, Y. et al. The role of the transcriptional regulator PTF1A in converting intestinal to pancreatic progenitors. Nat. Genet. 32, 128–134 (2002).

    Article  CAS  Google Scholar 

  6. Cockell, M. et al. Identification of a cell-specific DNA-binding activity that interacts with a transcriptional activator of genes expressed in the Acinar pancreas. Mol. Cell. Biol. 9, 2464–2476 (1989).

    Article  CAS  Google Scholar 

  7. Krapp, A. et al. The p48 DNA-binding subunit of transcription factor PTF1 is a new exocrine pancreas-specific basic helix-loop-helix-protein. EMBO J. 15, 4317–4329 (1996).

    Article  CAS  Google Scholar 

  8. Obata, J. et al. p48 subunit of mouse PTF1 binds to RBP-Jκ/CBF-1, the intracellular mediator of Notch signalling, and is expressed in the neural tube of early stage embryos. Genes Cells 6, 345–360 (2001).

    Article  CAS  Google Scholar 

  9. Rose, S.D. et al. The role of PTF1-P48 in pancreatic acinar gene expression. J. Biol. Chem. 276, 44018–44026 (2001).

    Article  CAS  Google Scholar 

  10. Zecchin, E. et al. Evolutionary conserved role of PTF1A in the specification of exocrine pancreatic fates. Dev. Biol. 268, 174–184 (2004).

    Article  CAS  Google Scholar 

  11. Njølstad, P.R. et al. Neonatal diabetes mellitus due to complete glucokinase deficiency. N. Engl. J. Med. 344, 1588–1592 (2001).

    Article  Google Scholar 

  12. Njølstad, P.R. et al. Permanent neonatal diabetes caused by glucokinase deficiency: inborn error of glucose-insulin signalling pathway. Diabetes 52, 2854–2860 (2003).

    Article  Google Scholar 

  13. Gloyn, A.L. et al. Activating mutations in the gene encoding the ATP-Sensitive potassium-channel subunit Kir6.2 and permanent neonatal diabetes. N. Engl. J. Med. 350, 1838–1849 (2004).

    Article  CAS  Google Scholar 

  14. Hoveyda, N. et al. Neonatal diabetes mellitus and cerebellar hypoplasia/agenesis: report of a new recessive syndrome. J. Med. Genet. 36, 700–704 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Kruglyak, L. et al. Rapid multipoint linkage analysis of recessive traits in nuclear families, including homozygosity mapping. Am. J. Hum. Genet. 56, 519–527 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Sigvardsson, M. Overlapping expression of early B-cell factor and basic helix-loop-helix proteins as a mechanism to dictate B-lineage-specific activity of the lambda5 promoter. Mol. Cell. Biol. 20, 3640–3654 (2000).

    Article  CAS  Google Scholar 

Download references


We thank members of the families for their collaboration, K. Meyer and M. Sigvardsson for the E47 expression vector, B. Spence-Dene for the murine Ptf1a cDNA clone and H. Spendlove for technical assistance. A.T.H. is a Wellcome Trust research leave fellow. This work was supported by the Institute of Cancer Research and grants to R.S.H. and G.G. from Cancer Research UK, and a grant from the Swiss National Science Foundation to P.K.W.

Author information

Authors and Affiliations


Corresponding author

Correspondence to Richard S Houlston.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Sellick, G., Barker, K., Stolte-Dijkstra, I. et al. Mutations in PTF1A cause pancreatic and cerebellar agenesis. Nat Genet 36, 1301–1305 (2004).

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI:

This article is cited by


Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing