Deficiency of PORCN, a regulator of Wnt signaling, is associated with focal dermal hypoplasia

Department of Human Genetics, University of Marburg, Bahnhofstr. 7, 35033 Marburg, Germany.
Nature Genetics (Impact Factor: 29.35). 08/2007; 39(7):833-5. DOI: 10.1038/ng2052
Source: PubMed

ABSTRACT Focal dermal hypoplasia (FDH) is an X-linked dominant multisystem birth defect affecting tissues of ectodermal and mesodermal origin. Using a stepwise approach of (i) genetic mapping of FDH, (ii) high-resolution comparative genome hybridization to seek deletions in candidate chromosome areas and (iii) point mutation analysis in candidate genes, we identified PORCN, encoding a putative O-acyltransferase and potentially crucial for cellular export of Wnt signaling proteins, as the gene mutated in FDH. The findings implicate FDH as a developmental disorder caused by a deficiency in PORCN.

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Available from: María del Carmen Boente, Jun 23, 2014
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    • "Intrafamilial variability has shown that a diagnosis in an individual may go unrecognized until the birth of a more severely affected child [Ruiz-Maldonado et al., 1974; Temple et al., 1990; Maas et al., 2009]. Lyonization has been suggested to explain the clinical variability of FDH [Grzeschik et al., 2007]. In the present family random X inactivation was observed in both mother and daughter. "
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    ABSTRACT: Focal dermal hypoplasia (FDH; Goltz-Gorlin syndrome) is an X-linked dominant disorder affecting mainly tissues of ectodermal and mesodermal origin. The phenotype is characterized by hypoplastic linear skin lesions, eye malformations, hair and teeth anomalies, and multiple limbs malformations. The disorder is caused by PORCN mutations. Here we describe a mother and daughter with FDH in whom a c.938T>G in PORCN was detected. Neither of the two had FDH, but otherwise the phenotype was classical. Focal skin hypoplasia is a hallmark of FDH but the present family indicates that FDH should also be considered in absence of this skin manifestation. © 2013 Wiley Periodicals, Inc.
    American Journal of Medical Genetics Part A 03/2014; 164(3). DOI:10.1002/ajmg.a.36341 · 2.16 Impact Factor
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    • "Porcn encodes an O-acyltransferase that palmitoylates all vertebrate Wnts at a conserved serine residue and is necessary for their secretion (Chen et al., 2009; Najdi et al., 2012; Proffitt and Virshup, 2012). PORCN mutations cause focal dermal hypoplasia in humans (Grzeschik et al., 2007; Wang et al., 2007), and the tissue defects in Porcn-null mice resemble those observed upon loss of single Wnts, including Wnt3, Wnt3a, Wnt5a, and Wnt7b (Barrott et al., 2011; Biechele et al., 2011, 2013; Liu et al., 2012). Thus, our approach circumvented the problem of redundancy that afflicts studies of single-Wnt gene disruption. "
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    ABSTRACT: Wnt signaling is a crucial aspect of the intestinal stem cell niche required for crypt cell proliferation and differentiation. Paneth cells or subepithelial myofibroblasts are leading candidate sources of the required Wnt ligands, but this has not been tested in vivo. To abolish Wnt-ligand secretion, we used Porcupine (Porcn) conditional-null mice crossed to strains expressing inducible Cre recombinase in the epithelium, including Paneth cells (Villin-Cre (ERT2) ); in smooth muscle, including subepithelial myofibroblasts (Myh11-Cre (ERT2) ); and simultaneously in both compartments. Elimination of Wnt secretion from any of these compartments did not disrupt tissue morphology, cell proliferation, differentiation, or Wnt pathway activity. Thus, Wnt-ligand secretion from these cell populations is dispensable for intestinal homeostasis, revealing that a minor cell type or significant and unexpected redundancy is responsible for physiologic Wnt signaling in vivo.
    Stem Cell Reports 02/2014; 2(2):127-34. DOI:10.1016/j.stemcr.2013.12.012 · 5.37 Impact Factor
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    • "Similar to mice, humans carry a single PORCN gene on the X chromosome (Xp11.23). Mutations in human PORCN cause FDH (Goltz Syndrome, OMIM#305600) [8,9], an X-linked dominant disorder characterized by dysplasias in ecto-mesodermal tissues. Phenotypically, FDH is characterized by patchy, hypoplastic skin, often along the lines of Blaschko [10,11]. "
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    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.
    PLoS ONE 11/2013; 8(11):e79139. DOI:10.1371/journal.pone.0079139 · 3.23 Impact Factor
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