Focal dermal hypoplasia resulting from a new nonsense mutation, p.E300X, in the PORCN gene

St. John's Institute of Dermatology, Division of Genetics and Molecular Medicine, The Guy's, King's College, St Thomas' School of Medicine, Guy's Hospital, London Bridge, London, UK.
Journal of Dermatological Science (Impact Factor: 3.42). 01/2008; 49(1):39-42. DOI: 10.1016/j.jdermsci.2007.09.004
Source: PubMed


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.

8 Reads
  • Source
    • "We and others first described that FDH is caused by mutations in the X-linked PORCN gene, which has facilitated the clinical diagnosis of FDH [8], [9], [10], [11], [12], [13]. Females with FDH have heterozygous or mosaic loss-of-function mutations or large deletions of PORCN and the few affected males have mosaic mutations [14]. "
    [Show abstract] [Hide abstract]
    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 · 3.23 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: The digitized partial discharge (PD) signal recorded at one power cable end consists of a sequence of pulses whose separation time contains information on the relative location of the PD sites. However, noisy PD signals can lead to a large PD site estimation error. The most annoying noise encountered during PD measurements consists primarily of amplitude modulated (AM) radio signals. The performance and the resolution of the wide band PD detection system are critically affected by this noise. This paper describes an adaptive noise mitigating system (ANMS) which is aimed at effectively reducing this noise
    Electrical Insulation, 1996., Conference Record of the 1996 IEEE International Symposium on; 07/1996
  • [Show abstract] [Hide abstract]
    ABSTRACT: The paper presents a generic model of the communication software for the class of telecontrol protocols dedicated to distributed control networks. The approach assumes object orientation and reusability. The model usage is supported by the related developer's guideline
    EUROMICRO 97. 'New Frontiers of Information Technology'. Short Contributions., Proceedings of the 23rd Euromicro Conference; 10/1997
Show more