Article

Novel PORCN mutations in focal dermal hypoplasia.

Human Genome Laboratory, Department for Molecular and Developmental Genetics, VIB, 3000 Leuven, Belgium.
Clinical Genetics (Impact Factor: 3.65). 10/2009; 76(6):535-43. DOI: 10.1111/j.1399-0004.2009.01248.x
Source: PubMed

ABSTRACT Focal dermal hypoplasia (FDH), Goltz or Goltz-Gorlin syndrome, is an X-linked dominant multisystem disorder characterized primarily by involvement of the skin, skeletal system and eyes. We screened for mutations in the PORCN gene in eight patients of Belgian and Finnish origin with firm clinical suspicion of FDH. First, we performed quantitative PCR (qPCR) analysis to define the copy number at this locus. Next, we sequenced the coding regions and flanking intronic sequences of the PORCN gene. Three de novo mutations were identified in our patients with FDH: a 150-kb deletion removing six genes including PORCN, as defined by qPCR and X-array-CGH, and two heterozygous missense mutations; c.992T>G (p.L331R) in exon 11 and c.1094G>A (p.R365Q) in exon 13 of the gene. Both point mutations changed highly conserved amino acids and were not found in 300 control X chromosomes. The three patients in whom mutations were identified all present with characteristic dermal findings together with limb manifestations, which were not seen in our mutation-negative patients. The clinical characteristics of our patients with PORCN mutations were compared with the previously reported mutation-positive cases. In this report, we summarize the literature on PORCN mutations and associated phenotypes.

0 Followers
 · 
147 Views
  • [Show abstract] [Hide abstract]
    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
  • [Show abstract] [Hide abstract]
    ABSTRACT: Goltz syndrome or Focal dermal hypoplasia (FDH) is an X-linked dominant disorder characterized by malformations affecting the skin, eyes, central nervous system, and skeletonC:\GetARef\Refs\focal dermal hypoplasia (2007-).re. Mutations in the PORCN gene were identified as the molecular basis of FDH. We report two cases, one caused by a current mutation c.129G>A, which leads to a nonsense mutation W43X, and the other one caused by a novel mutation, c.386delT. The female patient with the recurrent mutation presented with typical cutaneous symptoms and skeletal abnormality, but the female patient with the novel mutation manifested only cutaneous symptoms, with hypo-pigmentation along Blaschko's lines, mainly on her right hemibody. In the latter case, DNA was isolated from peripheral blood cells, lesional skin, and non-lesional skin. The percentage of cells carrying the mutation estimated by subcloning and sequencing of the PCR products was 3.1% in peripheral blood cells, 21% in lesional skin, and 16% in non-lesional skin. X-chromosome inactivation assay showed a slightly skewed pattern in lesional skin, but a random pattern in non-lesional skin and blood. RT-PCR analysis from skin samples showed that PORCN mRNA of the mutated allele had a 13bp nucleotide insertion created by an alternative splicing site. This resulted in abnormal PORCN protein with in-frame insertion of eight amino acids, TTHRGTDD, instead of the original four amino acids, AQMI (126-129). We report a typical FDH patient with a recurrent PORCN mutation, which was previously identified in a male Japanese FDH patient, and a second femal, an almost unilateral FDH patient with a postzygotic PORCN mutation.
    02/2013; 23(1). DOI:10.1684/ejd.2012.1911
  • [Show abstract] [Hide abstract]
    ABSTRACT: Wnts comprise a family of lipid-modified, secreted signaling proteins that control embryogenesis as well as tissue homeostasis in adults. Post-translational attachment of palmitoleate (C16:1) to a conserved Ser in Wnt proteins is catalyzed by Porcupine (Porcn), a member of the membrane bound O-acyltransferase (MBOAT) family, and is required for Wnt secretion and signaling. Moreover, genetic alterations in the PORCN gene lead to focal dermal hypoplasia (FDH), an X-linked developmental disorder. Despite its physiological importance, the biochemical mechanism governing Wnt acylation by Porcn is poorly understood. Here, we use a cell-based fatty acylation assay that is a direct readout of Porcn acyltransferase activity to perform structure-function analysis of highly conserved residues in Porcn and Wnt3a. In total, 16-point mutations in Porcn and 13 mutations in Wnt3a were generated and analyzed. We identified key residues within Porcn required for enzymatic activity, stability and Wnt3a binding, and mapped these active site residues to predicted transmembrane domain 9. Analysis of FDH-associated mutations in Porcn revealed that loss of enzymatic activity arises from altered stability. A consensus sequence within Wnt3a was identified (CXCHGXSXXCXXKXC) that contains residues that mediate Porcn binding, fatty acid transfer and Wnt signaling. We also showed that Ser or Thr, but not Cys, can serve as a fatty acylation site in Wnt, establishing Porcn as an O-acyltransferase. This analysis sheds light into the mechanism by which Porcn transfers fatty acids to Wnt proteins and provides insight into the mechanisms of fatty acid transfer by MBOAT family members.
    Journal of Biological Chemistry 05/2014; 289(24). DOI:10.1074/jbc.M114.561209 · 4.60 Impact Factor