title: 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 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.
authors.affiliation: Section of Cancer Genetics, Institute of Cancer Research, Surrey SM2 5NG, UK.
authors.forename: Gabrielle S
authors.initials: GS
authors.lastname: Sellick
authors.forename: Karen T
authors.initials: KT
authors.lastname: Barker
authors.forename: Irene
authors.initials: I
authors.lastname: Stolte-Dijkstra
authors.forename: Christina
authors.initials: C
authors.lastname: Fleischmann
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Coleman
authors.forename: Christine
authors.initials: C
authors.lastname: Garrett
authors.forename: Anna L
authors.initials: AL
authors.lastname: Gloyn
authors.forename: Emma L
authors.initials: EL
authors.lastname: Edghill
authors.forename: Andrew T
authors.initials: AT
authors.lastname: Hattersley
authors.forename: Peter K
authors.initials: PK
authors.lastname: Wellauer
authors.forename: Graham
authors.initials: G
authors.lastname: Goodwin
authors.forename: Richard S
authors.initials: RS
authors.lastname: Houlston
mesh_terms: D000818:Animals; D001483:Base Sequence; D015153:Blotting, Western; D002531:Cerebellum / Q000473:pathology; D002879:Chromosomes, Human, Pair 10 / Q000235:genetics*; D019295:Computational Biology; D003241:Consanguinity; D003920:Diabetes Mellitus / Q000235:genetics*; D008040:Genetic Linkage; D006652:Histological Techniques; D006801:Humans; D007223:Infant; D008126:Lod Score; D051379:Mice; D008817:Mice, Mutant Strains; D018895:Microsatellite Repeats / Q000235:genetics; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics*; D010179:Pancreas / Q000473:pathology; D010375:Pedigree; D010641:Phenotype; D017422:Sequence Analysis, DNA; D014157:Transcription Factors / Q000235:genetics*
chemical_list: D014157:Transcription Factors; C062602:transcription factor PTF1