Mutations in PTF1A cause pancreatic and cerebellar agenesis

Nat Genet. 2004 Dec;36(12):1301-5. doi: 10.1038/ng1475. Epub 2004 Nov 14.


Individuals with permanent neonatal diabetes mellitus usually present within the first three months of life and require insulin treatment. 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 family. 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 1alpha, 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 development, 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Base Sequence
  • Blotting, Western
  • Cerebellum / pathology
  • Chromosomes, Human, Pair 10 / genetics*
  • Computational Biology
  • Consanguinity
  • Diabetes Mellitus / genetics*
  • Genetic Linkage
  • Histological Techniques
  • Humans
  • Infant
  • Lod Score
  • Mice
  • Mice, Mutant Strains
  • Microsatellite Repeats / genetics
  • Molecular Sequence Data
  • Mutation / genetics*
  • Pancreas / pathology
  • Pedigree
  • Phenotype*
  • Sequence Analysis, DNA
  • Transcription Factors / genetics*


  • Transcription Factors
  • transcription factor PTF1

Associated data

  • GENBANK/AAO92259
  • GENBANK/AAQ74877
  • RefSeq/NM_178161
  • RefSeq/NP_061279
  • RefSeq/NP_446416
  • RefSeq/NP_835455