Focal dermal hypoplasia (Goltz syndrome).

Temple, I K; MacDowall, P; Baraitser, M; Atherton, D.J.

doi:10.1136/jmg.27.3.180

Cited by 101 publications

(81 citation statements)

References 18 publications

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“…The defining phenotype of FDH in humans is thin or absent dermis, which typically manifests at birth in discrete lesions ranging in size from millimeters to centimeters (20). Similarly, we observed large areas of dermal atrophy in a subset of Porcn Δ/+ embryos, such that internal organs, including liver and heart, were visible through an epidermal monolayer (Fig.…”

Section: Loss Of Porcn Causes a Cell-autonomous Defect In Wnt Ligandmentioning

confidence: 68%

“…3). As in the human syndrome, Porcn Δ/+ phenotypes varied widely in severity, most likely attributable to stochastic X-inactivation (20). For example, almost every heterozygous embryo examined exhibited one or more abnormal limbs, with defects ranging from digit loss or fusion to complete absence of autopod and ulna (Fig.…”

Section: Loss Of Porcn Causes a Cell-autonomous Defect In Wnt Ligandmentioning

confidence: 99%

“…Most patients with FDH are female heterozygotes, and the syndrome is never transmitted to male offspring, suggesting malespecific embryonic lethality. The congenital abnormalities associated with FDH are highly pleiotropic and variable, including multiple aspects of skin and skeletal development (20), and considerably overlap defects observed in mouse Wnt pathway mutants (Table S1). Given the connections between porcupine/ Porcn and Wnt signaling, we developed a conditional allele of mouse Porcn that provides a unique genetic tool to block Wnt ligand biogenesis.…”

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confidence: 99%

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Deletion of mouse Porcn blocks Wnt ligand secretion and reveals an ectodermal etiology of human focal dermal hypoplasia/Goltz syndrome

Barrott

Cash

Smith

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

159

157

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The Drosophila porcupine gene is required for secretion of wingless and other Wnt proteins, and sporadic mutations in its unique human ortholog, PORCN , cause a pleiotropic X-linked dominant disorder, focal dermal hypoplasia (FDH, also known as Goltz syndrome). We generated a conditional allele of the X-linked mouse Porcn gene and analyzed its requirement in Wnt signaling and embryonic development. We find that Porcn -deficient cells exhibit a cell-autonomous defect in Wnt ligand secretion but remain responsive to exogenous Wnts. Consistent with the female-specific inheritance pattern of FDH, Porcn hemizygous male embryos arrest during early embryogenesis and fail to generate mesoderm, a phenotype previously associated with loss of Wnt activity. Heterozygous Porcn mutant females exhibit a spectrum of limb, skin, and body patterning abnormalities resembling those observed in human patients with FDH. Many of these defects are recapitulated by ectoderm-specific deletion of Porcn , substantiating a long-standing hypothesis regarding the etiology of human FDH and extending previous studies that have focused on downstream elements of Wnt signaling, such as β-catenin. Conditional deletion of Porcn thus provides an experimental model of FDH, as well as a valuable tool to probe Wnt ligand function in vivo.

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Section: Loss Of Porcn Causes a Cell-autonomous Defect In Wnt Ligandmentioning

confidence: 68%

Section: Loss Of Porcn Causes a Cell-autonomous Defect In Wnt Ligandmentioning

confidence: 99%

mentioning

confidence: 99%

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Deletion of mouse Porcn blocks Wnt ligand secretion and reveals an ectodermal etiology of human focal dermal hypoplasia/Goltz syndrome

Barrott

Cash

Smith

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

159

157

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“…Stochastic X-linked inactivation leads to asymmetrical skeletal deformities such as syndactyly, absence or underdevelopment of digits or extremities, ectrodactyly, and polydactyly in various combinations. Additional abnormalities include osteopathia striata of long bones, scoliosis, and clavicular dysplasia (204). No human disease has yet been directly associated with WLS, but SNPs have been identified within an intron of WLS that are associated with BMD in Asian and European populations (205,206).…”

Section: Porcupine and Wntlessmentioning

confidence: 99%

A Comprehensive Overview of Skeletal Phenotypes Associated with Alterations in Wnt/β-catenin Signaling in Humans and Mice

2013

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The Wnt signaling pathway plays key roles in differentiation and development and alterations in this signaling pathway are causally associated with numerous human diseases. While several laboratories were examining roles for Wnt signaling in skeletal development during the 1990s, interest in the pathway rose exponentially when three key papers were published in 2001-2002. One report found that loss of the Wnt co-receptor, Low-density lipoprotein related protein-5 (LRP5), was the underlying genetic cause of the syndrome Osteoporosis pseudoglioma (OPPG). OPPG is characterized by early-onset osteoporosis causing increased susceptibility to debilitating fractures. Shortly thereafter, two groups reported that individuals carrying a specific point mutation in LRP5 (G171V) develop high-bone mass. Subsequent to this, the causative mechanisms for these observations heightened the need to understand the mechanisms by which Wnt signaling controlled bone development and homeostasis and encouraged significant investment from biotechnology and pharmaceutical companies to develop methods to activate Wnt signaling to increase bone mass to treat osteoporosis and other bone disease. In this review, we will briefly summarize the cellular mechanisms underlying Wnt signaling and discuss the observations related to OPPG and the high-bone mass disorders that heightened the appreciation of the role of Wnt signaling in normal bone development and homeostasis. We will then present a comprehensive overview of the core components of the pathway with an emphasis on the phenotypes associated with mice carrying genetically engineered mutations in these genes and clinical observations that further link alterations in the pathway to changes in human bone. Keywords: Wnt signaling; mouse models; Lrp5/Lrp6; β-catenin; skeletal phenotypes Bone Research (2013) 1: 27-71. doi: 10.4248/BR201301004 Overview of Wnt signal transductionWnts are a family of 19 mammalian proteins characterized by a conserved pattern of cysteine residues( 1). Wnts can activate several signaling pathways after binding to their cognate receptors, however, the bulk of this review will focus on the best characterized of these pathways, the so-called canonical pathway (Figure 1). This pathway results in the stabilization of the β-catenin protein and subsequent transactivation of target genes (2). It is initiated by Wnt ligands binding to a receptor complex that includes a member of the Frizzled (Fzd) family of seven-transmembrane receptors and either Lrp5, or the related Lrp6 protein(3). Engagement of this complex results in the phosphorylation of the cytoplasmic domain of Lrp5 or Lrp6, creating a binding site for the Axin protein.In the absence of an upstreamsignal, Axin exists in a multiprotein complex that also includes Adenomatous polyposis coli (APC) and the serine/ threonine protein kinase, Glycogen synthase kinase 3 α/β. This complex facilitates β-catenin for GSK3-dependent phosphorylation, targeting it for ubiquitin-depen- 28 dent proteolysis. Binding of Axin to phosphoryl...

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“…6 Rare male cases have been reported and this is thought to be caused by half-chromatid mutations. 9 Each of the cases described here presented with typical systemic oral and dental defects; in addition each case had a tooth affected by an area of external root resorption. This may have been an incidental finding or part of the dysplasia seen in this syndrome.…”

Section: Discussionmentioning

confidence: 99%

Dental and oral lesions in two patients with focal dermal hypoplasia (Goltz syndrome)

Baxter¹,

Shaw²,

Warren³

2000

Br Dent J

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Focal dermal hypoplasia (Goltz syndrome).

Cited by 101 publications

References 18 publications

Deletion of mouse Porcn blocks Wnt ligand secretion and reveals an ectodermal etiology of human focal dermal hypoplasia/Goltz syndrome

Deletion of mouse Porcn blocks Wnt ligand secretion and reveals an ectodermal etiology of human focal dermal hypoplasia/Goltz syndrome

A Comprehensive Overview of Skeletal Phenotypes Associated with Alterations in Wnt/β-catenin Signaling in Humans and Mice

Dental and oral lesions in two patients with focal dermal hypoplasia (Goltz syndrome)

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