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Ignatia B Van Den Veyver - One of the best experts on this subject based on the ideXlab platform.

  • a non mosaic porcn mutation in a male with severe congenital anomalies overlapping Focal Dermal Hypoplasia
    Molecular genetics and metabolism reports, 2017
    Co-Authors: Simran Madan, Reid V Sutton, Ignatia B Van Den Veyver, Wei Liu, Bryant A Toth, Priscilla Joe, John R Waterson, Richard A Gibbs, Edward J Lammer, Philippe M Campeau
    Abstract:

    Abstract Mutations in the PORCN gene cause the X-linked dominant condition Focal Dermal Hypoplasia (FDH). Features of FDH include striated pigmentation of the skin, ocular and skeletal malformations. FDH is generally associated with in utero lethality in non-mosaic males and most of the currently reported male patients show mosaicism due to de novo post-zygotic mutations in the PORCN gene. There is only one previous report of a surviving male with an inherited mutation in the PORCN gene. Here, we report two male siblings with multiple malformations including skeletal, ocular and renal defects overlapping with FDH. A novel PORCN mutation (p.Ser250Phe) was identified in a non-mosaic, hemizygous state in one of the siblings who survived to 8 years of age. The mother is a heterozygous carrier, has a random X-inactivation pattern and is asymptomatic. Findings unusual for FDH include dysplastic clavicles and bilateral Tessier IV facial clefts. This is the second case report of a non-mosaic PORCN mutation in a male individual with multiple congenital anomalies. While the pathogenicity of this mutation remains to be further investigated, the survival of a male with a non-mosaic mutation in PORCN is suggestive of a functionally mild mutation leading to an X-linked recessive mode of inheritance.

  • a rare human syndrome provides genetic evidence that wnt signaling is required for reprogramming of fibroblasts to induced pluripotent stem cells
    Cell Reports, 2014
    Co-Authors: J S Ross, Reid V Sutton, Ignatia B Van Den Veyver, Julia Busch, Ellen Mintz, Alexandra Stanley, David A Brafman, Karl Willert
    Abstract:

    WNT signaling promotes the reprogramming of somatic cells to an induced pluripotent state. We provide genetic evidence that WNT signaling is a requisite step during the induction of pluripotency. Fibroblasts from individuals with Focal Dermal Hypoplasia (FDH), a rare genetic syndrome caused by mutations in the essential WNT processing enzyme PORCN, fail to reprogram with standard methods. This blockade in reprogramming is overcome by ectopic WNT signaling and PORCN overexpression, thus demonstrating that WNT signaling is essential for reprogramming. The rescue of reprogramming is critically dependent on the level of WNT signaling: steady baseline activation of the WNT pathway yields karyotypically normal iPSCs, whereas daily stimulation with Wnt3a produces FDH-iPSCs with severely abnormal karyotypes. Therefore, although WNT signaling is required for cellular reprogramming, inappropriate activation of WNT signaling induces chromosomal instability, highlighting the precarious nature of ectopic WNT activation and its tight relationship with oncogenic transformation.

  • deletion of porcn in mice leads to multiple developmental defects and models human Focal Dermal Hypoplasia goltz syndrome
    PLOS ONE, 2012
    Co-Authors: Wei Liu, Xiaoling Wang, Ignatia B Van Den Veyver, Timothy M Shaver, Alfred Balasa, Cecilia M Ljungberg, Shu Wen, Hoang Nguyen
    Abstract:

    Background 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.

  • mutations in x linked porcn a putative regulator of wnt signaling cause Focal Dermal Hypoplasia
    Nature Genetics, 2007
    Co-Authors: Xiaoling Wang, Ping Fang, Ankita Patel, Reid V Sutton, Omar J Perazallanes, Rebecca Rosetta, Yingchuck Kou, Tanya N Eble, Christina Thaller, Ignatia B Van Den Veyver
    Abstract:

    Focal Dermal Hypoplasia is an X-linked dominant disorder characterized by patchy hypoplastic skin and digital, ocular and dental malformations. We used array comparative genomic hybridization to identify a 219-kb deletion in Xp11.23 in two affected females. We sequenced genes in this region and found heterozygous and mosaic mutations in PORCN in other affected females and males, respectively. PORCN encodes the human homolog of Drosophila melanogaster porcupine, an endoplasmic reticulum protein involved in secretion of Wnt proteins.

  • Deletion of Porcn in mice leads to multiple developmental defects and models human Focal Dermal Hypoplasia (Goltz syndrome).
    Public Library of Science (PLoS), 2026
    Co-Authors: Wei Liu, Xiaoling Wang, Timothy M Shaver, Alfred Balasa, Cecilia M Ljungberg, Shu Wen, Hoang Nguyen, Ignatia B Van Den Veyver
    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

Christiane Spaich - One of the best experts on this subject based on the ideXlab platform.

  • Goltz–Gorlin (Focal Dermal Hypoplasia) and the microphthalmia with linear skin defects (MLS) syndrome: no evidence of genetic overlap
    European Journal of Human Genetics, 2009
    Co-Authors: Maybritt Harmsen, E Seemanova, Peter Meinecke, Dietmar Muller, Anita Rauch, Eva Rossier, Silvia Azzarello-burri, M Mar García González, Gabriele Gillessen-kaesbach, Christiane Spaich
    Abstract:

    Focal Dermal Hypoplasia (FDH) is an X-linked developmental disorder with male lethality characterized by patchy Dermal Hypoplasia, skeletal and dental malformations, and microphthalmia or anophthalmia. Recently, heterozygous loss-of-function mutations in the PORCN gene have been described to cause FDH. FDH shows some clinical overlap with the microphthalmia with linear skin defects (MLS) syndrome, another X-linked male lethal condition, associated with mutations of HCCS in the majority of cases. We performed DNA sequencing of PORCN in 13 female patients with the clinical diagnosis of FDH as well as four female patients with MLS syndrome and no mutation in HCCS . We identified PORCN mutations in all female patients with FDH. Eleven patients seem to have constitutional PORCN alterations in the heterozygous state and two individuals are mosaic for the heterozygous sequence change in PORCN . No PORCN mutation was identified in the MLS-affected patients, providing further evidence that FDH and MLS do not overlap genetically. X chromosome inactivation (XCI) analysis revealed a random or slightly skewed XCI pattern in leukocytes of individuals with intragenic PORCN mutation suggesting that defective PORCN does not lead to selective growth disadvantage, at least in leukocytes. We conclude that the PORCN mutation detection rate is high in individuals with a clear-cut FDH phenotype and somatic mosaicism can be present in a significant proportion of patients with mild or classic FDH.

  • goltz gorlin Focal Dermal Hypoplasia and the microphthalmia with linear skin defects mls syndrome no evidence of genetic overlap
    European Journal of Human Genetics, 2009
    Co-Authors: Maybritt Harmsen, Gabriele Gillessenkaesbach, E Seemanova, Silvia Azzarelloburri, Mar Garcia M Gonzalez, Peter Meinecke, Dietmar Muller, Anita Rauch, Eva Rossier, Christiane Spaich
    Abstract:

    Focal Dermal Hypoplasia (FDH) is an X-linked developmental disorder with male lethality characterized by patchy Dermal Hypoplasia, skeletal and dental malformations, and microphthalmia or anophthalmia. Recently, heterozygous loss-of-function mutations in the PORCN gene have been described to cause FDH. FDH shows some clinical overlap with the microphthalmia with linear skin defects (MLS) syndrome, another X-linked male lethal condition, associated with mutations of HCCS in the majority of cases. We performed DNA sequencing of PORCN in 13 female patients with the clinical diagnosis of FDH as well as four female patients with MLS syndrome and no mutation in HCCS. We identified PORCN mutations in all female patients with FDH. Eleven patients seem to have constitutional PORCN alterations in the heterozygous state and two individuals are mosaic for the heterozygous sequence change in PORCN. No PORCN mutation was identified in the MLS-affected patients, providing further evidence that FDH and MLS do not overlap genetically. X chromosome inactivation (XCI) analysis revealed a random or slightly skewed XCI pattern in leukocytes of individuals with intragenic PORCN mutation suggesting that defective PORCN does not lead to selective growth disadvantage, at least in leukocytes. We conclude that the PORCN mutation detection rate is high in individuals with a clear-cut FDH phenotype and somatic mosaicism can be present in a significant proportion of patients with mild or classic FDH.

H Theile - One of the best experts on this subject based on the ideXlab platform.

  • midas syndrome microphthalmia Dermal aplasia and sclerocornea an autonomous entity with linear skin defects within the spectrum of Focal Hypoplasias
    European Journal of Dermatology, 1995
    Co-Authors: J Mucke, W Hoepffner, B Thamm, H Theile
    Abstract:

    The MIDAS syndrome (microphthalmia, Dermal aplasia, sclerocornea) is an X-linked dominant entity lethal for hemizygous male embryos. The aplasia of skin is exclusively localized on the face and the neck and follows the lines of Blaschko. Unlike the features observed in Focal Dermal Hypoplasia (Goltz syndrome), herniation of fatty tissue is absent. In addition to the 3 main symptoms mentioned above, other anomalies such as short stature are often present. We report this syndrome in a mother and her daughter who showed trikingly similar features. This family observation confirms the autonomy of MIDAS syndrome. Apparently this phenotype does not represent a particular form of lyonization of the gene responsible for Focal Dermal Hypoplasia. The phenotype should also be distinguished from Aicardi syndrome that is localized on Xp22

Maybritt Harmsen - One of the best experts on this subject based on the ideXlab platform.

  • Goltz–Gorlin (Focal Dermal Hypoplasia) and the microphthalmia with linear skin defects (MLS) syndrome: no evidence of genetic overlap
    European Journal of Human Genetics, 2009
    Co-Authors: Maybritt Harmsen, E Seemanova, Peter Meinecke, Dietmar Muller, Anita Rauch, Eva Rossier, Silvia Azzarello-burri, M Mar García González, Gabriele Gillessen-kaesbach, Christiane Spaich
    Abstract:

    Focal Dermal Hypoplasia (FDH) is an X-linked developmental disorder with male lethality characterized by patchy Dermal Hypoplasia, skeletal and dental malformations, and microphthalmia or anophthalmia. Recently, heterozygous loss-of-function mutations in the PORCN gene have been described to cause FDH. FDH shows some clinical overlap with the microphthalmia with linear skin defects (MLS) syndrome, another X-linked male lethal condition, associated with mutations of HCCS in the majority of cases. We performed DNA sequencing of PORCN in 13 female patients with the clinical diagnosis of FDH as well as four female patients with MLS syndrome and no mutation in HCCS . We identified PORCN mutations in all female patients with FDH. Eleven patients seem to have constitutional PORCN alterations in the heterozygous state and two individuals are mosaic for the heterozygous sequence change in PORCN . No PORCN mutation was identified in the MLS-affected patients, providing further evidence that FDH and MLS do not overlap genetically. X chromosome inactivation (XCI) analysis revealed a random or slightly skewed XCI pattern in leukocytes of individuals with intragenic PORCN mutation suggesting that defective PORCN does not lead to selective growth disadvantage, at least in leukocytes. We conclude that the PORCN mutation detection rate is high in individuals with a clear-cut FDH phenotype and somatic mosaicism can be present in a significant proportion of patients with mild or classic FDH.

  • goltz gorlin Focal Dermal Hypoplasia and the microphthalmia with linear skin defects mls syndrome no evidence of genetic overlap
    European Journal of Human Genetics, 2009
    Co-Authors: Maybritt Harmsen, Gabriele Gillessenkaesbach, E Seemanova, Silvia Azzarelloburri, Mar Garcia M Gonzalez, Peter Meinecke, Dietmar Muller, Anita Rauch, Eva Rossier, Christiane Spaich
    Abstract:

    Focal Dermal Hypoplasia (FDH) is an X-linked developmental disorder with male lethality characterized by patchy Dermal Hypoplasia, skeletal and dental malformations, and microphthalmia or anophthalmia. Recently, heterozygous loss-of-function mutations in the PORCN gene have been described to cause FDH. FDH shows some clinical overlap with the microphthalmia with linear skin defects (MLS) syndrome, another X-linked male lethal condition, associated with mutations of HCCS in the majority of cases. We performed DNA sequencing of PORCN in 13 female patients with the clinical diagnosis of FDH as well as four female patients with MLS syndrome and no mutation in HCCS. We identified PORCN mutations in all female patients with FDH. Eleven patients seem to have constitutional PORCN alterations in the heterozygous state and two individuals are mosaic for the heterozygous sequence change in PORCN. No PORCN mutation was identified in the MLS-affected patients, providing further evidence that FDH and MLS do not overlap genetically. X chromosome inactivation (XCI) analysis revealed a random or slightly skewed XCI pattern in leukocytes of individuals with intragenic PORCN mutation suggesting that defective PORCN does not lead to selective growth disadvantage, at least in leukocytes. We conclude that the PORCN mutation detection rate is high in individuals with a clear-cut FDH phenotype and somatic mosaicism can be present in a significant proportion of patients with mild or classic FDH.

Raoul C Hennekam - One of the best experts on this subject based on the ideXlab platform.

  • Focal Dermal Hypoplasia without Focal Dermal Hypoplasia.
    American journal of medical genetics. Part A, 2013
    Co-Authors: Silvina N Contreras-capetillo, Maria Paola Lombardi, Doris Pinto-escalante, Raoul C Hennekam
    Abstract:

    Focal Dermal Hypoplasia (FDH; Goltz-Gorlin syndrome) is an X-linked dominant disorder affecting mainly tissues of ectoDermal and mesoDermal origin. The phenotype is characterized by hypoplastic linear skin lesions, eye malformations, hair and teeth anomalies, and multiple limbs malformations. The disorder is caused by PORCN mutations. Here we describe a mother and daughter with FDH in whom a c.938T>G in PORCN was detected. Neither of the two had FDH, but otherwise the phenotype was classical. Focal skin Hypoplasia is a hallmark of FDH but the present family indicates that FDH should also be considered in absence of this skin manifestation.