Nature Genetics
36, 1301 - 1305 (2004)
Published online: 14 November 2004; | doi:10.1038/ng1475
Mutations in PTF1A cause pancreatic and cerebellar agenesisGabrielle S Sellick1, Karen T Barker1, Irene Stolte-Dijkstra2, Christina Fleischmann1, Richard J Coleman1, Christine Garrett3, Anna L Gloyn4, Emma L Edghill4, Andrew T Hattersley4, Peter K Wellauer5, Graham Goodwin6
& Richard S Houlston11
Section of Cancer Genetics, Institute of Cancer Research, Surrey SM2 5NG, UK. 2
Department of Clinical Genetics, University Hospital Groningen, Groningen 9700 RB, The Netherlands. 3
North West Thames Regional Genetics Service, Kennedy-Galton Centre, North West London Hospitals NHS Trust, Harrow HA1 3UJ, UK. 4
Diabetes and Vascular Medicine, Peninsula Medical School, Exeter EX2 5AX, UK. 5
Swiss Institute for Experimental Cancer Research (ISREC), CH-1066 Epalinges, Switzerland. 6
Section of Molecular Carcinogenesis, Institute of Cancer Research, Surrey SM2 5NG, UK.
Correspondence should be addressed to Richard S Houlston Richard.Houlston@icr.ac.ukIndividuals 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 1 , 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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