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Mutations in PTF1A cause pancreatic and cerebellar agenesis

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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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.

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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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Correspondence to Richard S Houlston.

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Sellick, G., Barker, K., Stolte-Dijkstra, I. et al. Mutations in PTF1A cause pancreatic and cerebellar agenesis. Nat Genet 36, 1301–1305 (2004). https://doi.org/10.1038/ng1475

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