<i>PORCN</i>mutations in focal dermal hypoplasia: coping with lethality

Bornholdt, Dorothea; Oeffner, Frank; König, A.; Happle, Rudolf; Alanay, Yasemin; Ascherman, Jeffrey A.; Benke, PJ; Boente,; Burgt, Ineke van der; Chassaing, Nicolas; Ellis, Ian; Francisco, Cri; Giovanna, Patricia Della; Hamel, B.C.J.; Has, Cristina; Heinelt, Kaatje; Janecke, Andreas; Kastrup, Wolfgang; Loeys, Bart; Lohrisch, Ingo; Marcelis, Carlo; Mehraein, Yasmin; Nicolas, Meo; Pagliarini, D; Paradisi, Mauro; Patrizi, Annalisa; Piccione, Maria; Piza‐Katzer, Hildegunde; Prager, Bettina; Prescott, Katrina; Strien, J; Ge, Utine; Zeller, Andreas; Kh, Grzeschik

doi:10.1002/humu.21125

Cited by 27 publications

(50 citation statements)

References 0 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Studies of inheritance and X-inactivation in human patients have suggested that only the least-affected patients with FDH survive beyond birth (19), and our data strongly support this model: Most Porcn Δ/+ mice appear to die perinatally, and the only postnatal survivor yet obtained had an extremely mild phenotype compared with embryos. As in FDH, the defects in Porcn Δ/+ embryos are typically discrete and asymmetrical, presumably reflecting domains of Porcn-deficient cells established by X-inactivation.…”

Section: Discussionsupporting

confidence: 74%

“…S2E). The defective endogenous Wnt response of Porcn Δ cells was fully rescued by cotransfection with WT human PORCN, whereas a missense mutant observed in a patient with FDH, affecting the putative active site histidine (H341L) (19), had no rescuing activity ( Fig. 2A).…”

Section: Resultsmentioning

confidence: 99%

“…305600) (17)(18)(19). Most patients with FDH are female heterozygotes, and the syndrome is never transmitted to male offspring, suggesting malespecific embryonic lethality.…”

mentioning

confidence: 99%

See 2 more Smart Citations

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.

157

154

View full text Add to dashboard Cite

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.

show abstract

Section: Discussionsupporting

confidence: 74%

Section: Resultsmentioning

confidence: 99%

See 1 more Smart Citation

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.

157

154

View full text Add to dashboard Cite

show abstract

“…In 2007, mutations were reported in PORCN at Xp11.23 [Grzeschlik et al, 2007;Wang et al, 2007]. Over 100 different PORCN mutations have been reported [Lombardi et al, submitted for publication; Bornholdt et al, 2009;Clements et al, 2009;Froyen et al, 2009]. …”

Section: Discussionmentioning

confidence: 96%

Co‐occurrence of severe Goltz–Gorlin syndrome and pentalogy of Cantrell – Case report and review of the literature

Śmigiel

Jakubiak

Lombardi

et al. 2011

American J of Med Genetics Pt A

View full text Add to dashboard Cite

Goltz-Gorlin syndrome is a highly variable disorder affecting many body parts of meso-ectodermal origin. Mutations in X-linked PORCN have been identified in almost all patients with a classical Goltz-Gorlin phenotype. The pentalogy of Cantrell is an infrequently described congenital disorder characterized by the combination of five anomalies: a midline supra-umbilical abdominal wall defect; absent or cleft lower part of the sternum; deficiency of the diaphragmatic pericardium; deficiency of the anterior diaphragm; and congenital heart anomalies. Etiology and pathogenesis are unknown. We report on an infant with findings fitting both Goltz-Gorlin syndrome (sparse hair; anophthalmia; clefting; bifid nose; irregular vermillion of both lips; asymmetrical limb malformations; caudal appendage; linear aplastic skin defects; unilateral hearing loss) and the pentalogy of Cantrell (absent lower sternum; anterior diaphragmatic hernia; ectopia cordis; omphalocele). The clinical diagnosis Goltz-Gorlin syndrome was confirmed molecularly by a point mutation in PORCN (c.727C>T). The presence of molecularly confirmed Goltz-Gorlin syndrome and pentalogy of Cantrell in a single patient has been reported twice before. The present patient confirms that the pentalogy of Cantrell can be caused in some patients by a PORCN mutation. It remains at present uncertain whether this can be explained by the type or localization of the mutation within PORCN, or whether the co-occurrence of the two entities is additionally determined by mutations or polymorphisms in other genes, environmental factors, and/or epigenetic influences.

show abstract

“…Finally, several females with focal dermal hypoplasia caused by mutations in the X-linked PORCN gene and submicroscopic deletions that include the adjacent EBP locus have been described ( 253,254 ). Interestingly, none of the females exhibited any features of CDPX2.…”

Section: Sterol Biochemistry and Molecular Biologymentioning

confidence: 99%