Focal dermal hypoplasia resulting from a new nonsense mutation, p.E300X, in the PORCN gene
ABSTRACT Focal dermal hypoplasia (FDH) (OMIM 305600) is an X-linked dominant disorder of ecto-mesodermal development. Also known as Goltz syndrome, FDH presents with characteristic linear streaks of hypoplastic dermis and variable abnormalities of bone, nails, hair, limbs, teeth and eyes. The molecular basis of FDH involves mutations in the PORCN gene, which encodes an enzyme that allows membrane targeting and secretion of several Wnt proteins critical for normal tissue development.
To investigate the molecular basis of FDH in a 2-year-old Thai girl who presented at birth with depressed, pale linear scars on the trunk and limbs, sparse brittle hair, syndactyly of the right middle and ring fingers, dental caries and radiological features of osteopathia striata.
Sequencing of genomic DNA from the affected individual and both parents to search for pathogenic mutations in PORCN gene.
DNA sequencing disclosed a heterozygous G>T substitution at nucleotide c.898 within exon 10 (NM_203475.1), converting a glutamic acid residue (GAA) to a premature termination codon (TAA). This mutation, designated p.E300X, was not detected in DNA from either parent or in 100 control chromosomes.
Identification of this new de novo nonsense mutation confirms the diagnosis of FDH in this child and highlights the clinical importance of PORCN and Wnt signalling pathways in embryogenesis.
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ABSTRACT: Focal 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. We 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. These 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.PLoS ONE 03/2012; 7(3):e32331. DOI:10.1371/journal.pone.0032331 · 3.53 Impact Factor
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ABSTRACT: Focal dermal hypoplasia (FDH), or Goltz syndrome, is a rare X-linked dominant ectodermal and mesodermal disease involving the skin, distal limbs, and eyes. About 95% of the cases appear de novo, and 90% are females. Recent studies reveal that FDH is caused by mutations in the PORCN gene. Female patients are either heterozygous or mosaic for PORCN mutations, whereas all male patients are mosaic. About 5% of the female patients analyzed have no detectable mutations or microdeletions of PORCN gene. We report a sporadic case of FDH in a 16-year-old girl presenting with atrophic or erythematous macules and patches distributed along the lines of Blaschko over the trunk and extremities with prominent soft yellowish fat herniation over the left axilla and left groin, and papillomas in the oral and genital areas. Multiple developmental anomalies of the digits and ear were also noted. Histopathology of the skin lesion revealed severe dermal hypoplasia. Mutation analysis of all coding regions and flanking intron boundaries of the genomic DNA revealed no detectable mutation of the PORCN gene. Our case manifested mucocutaneous and multiple developmental anomalies typical of FDH, but no mutation in the PORCN gene was detected by mutation analysis.Dermatologica Sinica 06/2011; 29(2):59-62. DOI:10.1016/j.dsi.2011.05.004 · 0.57 Impact Factor
Acta Dermato-Venereologica 06/2012; 93(1). DOI:10.2340/00015555-1399 · 4.24 Impact Factor