Cookies on this website
We use cookies to ensure that we give you the best experience on our website. If you click 'Continue' we'll assume that you are happy to receive all cookies and you won't see this message again. Click 'Find out more' for information on how to change your cookie settings.

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.

Original publication

DOI

10.1038/ng1475

Type

Journal article

Journal

Nat Genet

Publication Date

12/2004

Volume

36

Pages

1301 - 1305

Keywords

Animals, Base Sequence, Blotting, Western, Cerebellum, Chromosomes, Human, Pair 10, Computational Biology, Consanguinity, Diabetes Mellitus, Genetic Linkage, Histological Techniques, Humans, Infant, Lod Score, Mice, Mice, Mutant Strains, Microsatellite Repeats, Molecular Sequence Data, Mutation, Pancreas, Pedigree, Phenotype, Sequence Analysis, DNA, Transcription Factors