Mutations in PTF1A cause pancreatic and cerebellar agenesis.
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.
Sellick
Gabrielle S
GS
Section of Cancer Genetics, Institute of Cancer Research, Surrey SM2 5NG, UK.
Barker
Karen T
KT
Stolte-Dijkstra
Irene
I
Fleischmann
Christina
C
Coleman
Richard J
RJ
Garrett
Christine
C
Gloyn
Anna L
AL
Edghill
Emma L
EL
Hattersley
Andrew T
AT
Wellauer
Peter K
PK
Goodwin
Graham
G
Houlston
Richard S
RS
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*
D014157:Transcription Factors; C062602:transcription factor PTF1