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Zygotic Porcn paternal allele deletion in mice to model human focal dermal hypoplasia.

Biechele S, Adissu HA, Cox BJ, Rossant J - PLoS ONE (2013)

Bottom Line: This disorder is characterized by ecto-mesodermal dysplasias and shows a highly variable phenotype, potentially due to individual X chromosome inactivation patterns.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.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.

View Article: PubMed Central - PubMed

Affiliation: Program in Developmental and Stem Cell Biology, Hospital for Sick Children Research Institute, Toronto, Ontario, Canada ; Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada.

ABSTRACT
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.

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Body composition and skeletal phenotypes in adult Porcn+/del females.Adult Porcn+/del and Porcn+/+ females were subjected to X-ray imaging and body composition analysis. While fat mass (A) and lean mass (B) was not significantly different (t-test), bone mineral density (BMD, C) and bone mineral content (BMC, D) were significantly reduced in heterozygous females. X-ray imaging was unremarkable in both control (E) and heterozygous females (F). One out of the five analyzed heterozygous female exhibited a sternal gap (G, white arrowhead). Consistent with duplication of the sternal skeleton, osseous structures on either side were enveloped by periosteal tissue (H). Arrow indicates the border between left and right ribcage and the sternal gap is indicated by asterisk.
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pone-0079139-g006: Body composition and skeletal phenotypes in adult Porcn+/del females.Adult Porcn+/del and Porcn+/+ females were subjected to X-ray imaging and body composition analysis. While fat mass (A) and lean mass (B) was not significantly different (t-test), bone mineral density (BMD, C) and bone mineral content (BMC, D) were significantly reduced in heterozygous females. X-ray imaging was unremarkable in both control (E) and heterozygous females (F). One out of the five analyzed heterozygous female exhibited a sternal gap (G, white arrowhead). Consistent with duplication of the sternal skeleton, osseous structures on either side were enveloped by periosteal tissue (H). Arrow indicates the border between left and right ribcage and the sternal gap is indicated by asterisk.

Mentions: As human patients frequently present with skeletal abnormalities and reduced bone density [26,27], we performed body composition analyses, X-ray imaging and necropsies on Porcn+/del females. While we could not detect significant changes in fat and lean mass (Figure 6A, B), the bone mineral density (BMD) and bone mineral content (BMC) of mutant mice were significantly reduced (Figure 6C, D). X-ray imaging was largely unremarkable (Figure 6E, F), although necropsies identified one mouse with a thoracic body wall defect; the thorax exhibited a 10 mm wedge-shaped gap in the sternal bone (Figure 6G). The sternal osseous and cartilaginous structures on either side of the defect were each enveloped by differentiated periosteal and perichondrial tissue consistent with duplication of the sternal skeleton (Figure 6H). Strikingly, human FDH patients with split sternum have also been observed [27,28], highlighting the similarities between the mouse and human phenotypes.


Zygotic Porcn paternal allele deletion in mice to model human focal dermal hypoplasia.

Biechele S, Adissu HA, Cox BJ, Rossant J - PLoS ONE (2013)

Body composition and skeletal phenotypes in adult Porcn+/del females.Adult Porcn+/del and Porcn+/+ females were subjected to X-ray imaging and body composition analysis. While fat mass (A) and lean mass (B) was not significantly different (t-test), bone mineral density (BMD, C) and bone mineral content (BMC, D) were significantly reduced in heterozygous females. X-ray imaging was unremarkable in both control (E) and heterozygous females (F). One out of the five analyzed heterozygous female exhibited a sternal gap (G, white arrowhead). Consistent with duplication of the sternal skeleton, osseous structures on either side were enveloped by periosteal tissue (H). Arrow indicates the border between left and right ribcage and the sternal gap is indicated by asterisk.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3815152&req=5

pone-0079139-g006: Body composition and skeletal phenotypes in adult Porcn+/del females.Adult Porcn+/del and Porcn+/+ females were subjected to X-ray imaging and body composition analysis. While fat mass (A) and lean mass (B) was not significantly different (t-test), bone mineral density (BMD, C) and bone mineral content (BMC, D) were significantly reduced in heterozygous females. X-ray imaging was unremarkable in both control (E) and heterozygous females (F). One out of the five analyzed heterozygous female exhibited a sternal gap (G, white arrowhead). Consistent with duplication of the sternal skeleton, osseous structures on either side were enveloped by periosteal tissue (H). Arrow indicates the border between left and right ribcage and the sternal gap is indicated by asterisk.
Mentions: As human patients frequently present with skeletal abnormalities and reduced bone density [26,27], we performed body composition analyses, X-ray imaging and necropsies on Porcn+/del females. While we could not detect significant changes in fat and lean mass (Figure 6A, B), the bone mineral density (BMD) and bone mineral content (BMC) of mutant mice were significantly reduced (Figure 6C, D). X-ray imaging was largely unremarkable (Figure 6E, F), although necropsies identified one mouse with a thoracic body wall defect; the thorax exhibited a 10 mm wedge-shaped gap in the sternal bone (Figure 6G). The sternal osseous and cartilaginous structures on either side of the defect were each enveloped by differentiated periosteal and perichondrial tissue consistent with duplication of the sternal skeleton (Figure 6H). Strikingly, human FDH patients with split sternum have also been observed [27,28], highlighting the similarities between the mouse and human phenotypes.

Bottom Line: This disorder is characterized by ecto-mesodermal dysplasias and shows a highly variable phenotype, potentially due to individual X chromosome inactivation patterns.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.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.

View Article: PubMed Central - PubMed

Affiliation: Program in Developmental and Stem Cell Biology, Hospital for Sick Children Research Institute, Toronto, Ontario, Canada ; Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada.

ABSTRACT
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.

Show MeSH
Related in: MedlinePlus