Probable identity of Goltz syndrome and Van Allen‐Myhre syndrome: Evidence from phenotypic evolution

Hancock, Susan; Pryde, Peter G.; Fong, Christine; Brazy, Jane E.; Stewart, Katharina; Favour, Amy; Pauli, Richard M.

doi:10.1002/ajmg.10456

Cited by 18 publications

(10 citation statements)

References 25 publications

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“…3 G-J). These phenotypes recapitulate those of dermal-specific β-catenin KOs (35), as well as those attributed to severe cases of human FDH (20,36).…”

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

confidence: 67%

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.

161

154

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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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“…3 G-J). These phenotypes recapitulate those of dermal-specific β-catenin KOs (35), as well as those attributed to severe cases of human FDH (20,36).…”

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

confidence: 67%

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.

161

154

View full text Add to dashboard Cite

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“…In a given cell or tissue, only a subset of Wnt factors stimulates signal response (Logan and Nusse, 2004), and missense mutations detrimental for single PORCN isoforms might exclusively affect tissues determined by Wnt proteins activated by this isoenzyme. Traits expressing only part of the FDH phenotypic spectrum, such as Van Allen-Myhre syndrome (Hancock et al, 2002) and osteopathia striata with cranial sclerosis (MIM# 300373) (Behninger and Rott, 2000), are strong candidates for PORCN mutations.…”

Section: Resultsmentioning

confidence: 99%

PORCNmutations in focal dermal hypoplasia: coping with lethality

et al. 2009

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The X-linked dominant trait focal dermal hypoplasia (FDH, Goltz syndrome) is a developmental defect with focal distribution of affected tissues due to a block of Wnt signal transmission from cells carrying a detrimental PORCN mutation on an active X-chromosome. Molecular characterization of 24 unrelated patients from different ethnic backgrounds revealed 23 different mutations of the PORCN gene in Xp11.23. Three were microdeletions eliminating PORCN and encompassing neighboring genes such as EBP, the gene associated with ConradiHünermann-Happle syndrome (CDPX2). 12/24 patients carried nonsense mutations resulting in loss of function. In one case a canonical splice acceptor site was mutated, and 8 missense mutations exchanged highly conserved amino acids. FDH patients overcome the consequences of potentially lethal X-chromosomal mutations by extreme skewing of X-chromosome inactivation in females, enabling transmission of the trait in families, or by postzygotic mosaicism both in male and female individuals. Molecular characterization of the PORCN mutations in cases diagnosed as Goltz syndrome is particularly relevant for genetic counseling of patients and their families since E619 PORCN Mutations in FDHno functional diagnostic test is available and carriers of the mutation might otherwise be overlooked due to considerable phenotypic variability associated with the mosaic status. ©2009Wiley-Liss, Inc.

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“…Since then, at least 80 different mutations and large genomic deletions of the PORCN gene have been found in FDH patients [36]. The resulting phenotype in human patients varies widely from mild skin and distal skeletal defects to severe forms of FDH, with multiple defects that include severe limb abnormalities involving long bones, aplasia cutis, limb-body wall complex anomaly, pentalogy of Cantrell, and Van Allen-Myhre syndrome [35], [36], [47]. Identification and characterization of PORCN mutations as the cause of FDH was important for genetic counseling and diagnostic testing in suspected cases.…”

Section: Discussionmentioning

confidence: 99%

Deletion of Porcn in Mice Leads to Multiple Developmental Defects and Models Human Focal Dermal Hypoplasia (Goltz Syndrome)

et al. 2012

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BackgroundFocal Dermal Hypoplasia (FDH) is a genetic disorder characterized by developmental defects in skin, skeleton and ectodermal appendages. FDH is caused by dominant loss-of-function mutations in X-linked PORCN. PORCN orthologues in Drosophila and mice encode endoplasmic reticulum proteins required for secretion and function of Wnt proteins. Wnt proteins play important roles in embryo development, tissue homeostasis and stem cell maintenance. Since features of FDH overlap with those seen in mouse Wnt pathway mutants, FDH likely results from defective Wnt signaling but molecular mechanisms by which inactivation of PORCN affects Wnt signaling and manifestations of FDH remain to be elucidated.ResultsWe introduced intronic loxP sites and a neomycin gene in the mouse Porcn locus for conditional inactivation. Porcn-ex3-7flox mice have no apparent developmental defects, but chimeric mice retaining the neomycin gene (Porcn-ex3-7Neo-flox) have limb, skin, and urogenital abnormalities. Conditional Porcn inactivation by EIIa-driven or Hprt-driven Cre recombinase results in increased early embryonic lethality. Mesenchyme-specific Prx-Cre-driven inactivation of Porcn produces FDH-like limb defects, while ectodermal Krt14-Cre-driven inactivation produces thin skin, alopecia, and abnormal dentition. Furthermore, cell-based assays confirm that human PORCN mutations reduce WNT3A secretion.ConclusionsThese data indicate that Porcn inactivation in the mouse produces a model for human FDH and that phenotypic features result from defective WNT signaling in ectodermal- and mesenchymal-derived structures.

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Probable identity of Goltz syndrome and Van Allen‐Myhre syndrome: Evidence from phenotypic evolution

Cited by 18 publications

References 25 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

PORCNmutations in focal dermal hypoplasia: coping with lethality

Deletion of Porcn in Mice Leads to Multiple Developmental Defects and Models Human Focal Dermal Hypoplasia (Goltz Syndrome)

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