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In mouse and humans, the X-chromosomal Porcupine homolog (Porcn) gene is required for the acylation and secretion of all 19 Wnt ligands, thus representing a bottleneck in the secretion of Wnt ligands. In humans, mutations in PORCN cause the X-linked dominant syndrome Focal Dermal Hypoplasia (FDH, OMIM#305600). This disorder is characterized by ecto-mesodermal dysplasias and shows a highly variable phenotype, potentially due to individual X chromosome inactivation patterns. To improve the understanding of human FDH, we have established a mouse model by generation of Porcn heterozygous animals carrying a zygotic deletion of the paternal allele. We show that heterozygous female fetuses display variable defects that do not significantly affect survival in the uterus, but lead to perinatal lethality in more than 95% of females. Rare survivors develop to adulthood and display variable skeletal and skin defects, representing an adult zygotic mouse model for human FDH. Although not frequently reported in humans, we also observed bronchopneumonia, rhinitis, and otitis media in these animals, suggesting a potential link between Porcn function and the normal development of ciliated cells in these tissues.
Pubmed ID: 24223895 RIS Download
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Multidisciplinary collaboration undertaking genome-wide mutagenesis to functionally annotate the mouse genome and develop new mouse models relevant to human disease. To achieve these goals two major research platforms are carried out: Gene trapping and ENU Mutagenesis. A new challenge is faced in the post-genomic era - the assignment of biological function to the human genome sequence and projecting that assignment into understanding of human health and disease. The Centre for Modeling Human Disease (CMHD) was established to take part in the worldwide initiative to address these challenges. At the CMHD, two fundamentally different, yet complimentary methods are employed to generate mutant mouse models of human disease: chemical mutagenesis by ethylnitrosourea (ENU), and gene trap insertional mutagenesis. The Centre contributes its resources to similar international efforts and is the first of its kind in Canada. The Center is also actively developing other mutagenic strategies including pharmacologic and genetic modifier screens to dissect disease pathways, and novel mutagenic techniques using embryonic stem cells. ENU Database * Statistics for Mouse Physiological Parameters * Search Mutants by Phenotype * Search Mutants by Heritability Gene Trap Database * Search by in vitro Expression Pattern * Search by Gene Trap Sequences CMHD Members Only (must register and login) * Search Mouse Line * Histopathology * Sperm, Tissue, Slide Archiving * CMHD Database Download CMHD Services * Phenotyping * Genetic Mapping * Pathology * Pathology Service Charges
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