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Abstract

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.

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Acknowledgements

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.

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Affiliations

  1. Section of Cancer Genetics, Institute of Cancer Research, Surrey SM2 5NG, UK.

    • Gabrielle S Sellick
    • , Karen T Barker
    • , Christina Fleischmann
    • , Richard J Coleman
    •  & Richard S Houlston
  2. Department of Clinical Genetics, University Hospital Groningen, Groningen 9700 RB, The Netherlands.

    • Irene Stolte-Dijkstra
  3. North West Thames Regional Genetics Service, Kennedy-Galton Centre, North West London Hospitals NHS Trust, Harrow HA1 3UJ, UK.

    • Christine Garrett
  4. Diabetes and Vascular Medicine, Peninsula Medical School, Exeter EX2 5AX, UK.

    • Anna L Gloyn
    • , Emma L Edghill
    •  & Andrew T Hattersley
  5. Swiss Institute for Experimental Cancer Research (ISREC), CH-1066 Epalinges, Switzerland.

    • Peter K Wellauer
  6. Section of Molecular Carcinogenesis, Institute of Cancer Research, Surrey SM2 5NG, UK.

    • Graham Goodwin

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The authors declare no competing financial interests.

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Correspondence to Richard S Houlston.

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https://doi.org/10.1038/ng1475

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