Nature Genetics36, 1301 - 1305 (2004)
Published online: 14 November 2004; | doi:10.1038/ng1475
Mutations in PTF1A cause pancreatic and cerebellar agenesis
Gabrielle 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 Houlston1
1
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.
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 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.
MORE ARTICLES LIKE THIS
These links to content published by NPG are automatically generated.
, 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
