PORCNmutations in focal dermal hypoplasia: coping with lethality

Abstract

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.

Goltz syndrome in males: A clinical report of a male patient carrying a novel PORCN variant and a review of the literature

“…GS was long presumed to be lethal in males 13, 14. However, later reports have shown that approximately 10% of all GS patients are males 2, 15. The majority of surviving males can be explained by mosaicism for PORCN mutations that arise postzygotically during embryogenesis 16 or Klinefelter syndrome, since these males carry an additional X chromosome 5.…”

Expanding the phenotypic spectrum of PORCN variants in two males with syndromic microphthalmia

“…Pathogenic PORCN variants have previously been reported that affect the same transmembrane domain, which further supports the pathogenicity of the p.(Gly157Asp) variant. 5,[19][20][21] Variants in PORCN were first reported as a cause of FDH in 2007. 19, 22 Froyen et al later identified PORCN variants and gene deletions in a cohort of patients with a clinical diagnosis of FDH.…”

Porcupine homolog is required for canonical Wnt signaling and gastrulation in mouse embryos

“…The majority of FDH patients are females, and all male patients carry postzygotic mutations, making them mosaic for Porcn function. The absence of zygotic mutant male patients indicates likely embryonic lethality caused by complete lack of Porcn function in humans (Bornholdt et al, 2009). We have recently identified Porcn in a screen for X-chromosomal embryonic lethal genes in the mouse (Cox et al, 2010), providing evidence that Porcn is indeed required for mammalian embryonic development.…”