Deficiency of PORCN, a regulator of Wnt signaling, is associated with focal dermal hypoplasia

Grzeschik, K.-H.; Bornholdt, Dorothea; Oeffner, Frank; König, Arne; Boente, María del Carmen; Enders, Herbert; Fritz, Bárbara; Hertl, Michael; Grasshoff, Ute; Höfling, Katja; Oji, Vinzenz; Paradisi, Mauro; Schuchardt, Christian A.; Szalai, Zsuzsanna; Tadini, Gianluca; Traupe, Heiko; Happle, Rudolf

doi:10.1038/ng2052

Cited by 257 publications

(252 citation statements)

References 13 publications

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“…PORCN, a member of the porcupine family, is believed to encode an O-acetyltransferase that is required for the palmitoylation and subsequent secretion of Wnts; a necessary step for signaling. 76 In an independent line of research, using a comparative genomic hybridization based approach, a 219 kb region containing seven candidate genes was identified as being lost in one patient with focal dermal hypoplasia. Mutations in some of the 7 genes were previously associated with other syndromes.…”

Section: Adult Stem Cellsmentioning

confidence: 99%

Wnt signaling in skin organogenesis

Widelitz

2008

Organogenesis

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While serving as the interface between an organism and its environment, the skin also can elaborate a wide range of skin appendages to service specific purposes in a region-specific fashion. As in other organs, Wnt signaling plays a key role in regulating the proliferation, differentiation and motility of skin cells during their morphogenesis. Here I will review some of the recent work that has been done on skin organogenesis. I will cover dermis formation, the development of skin appendages, cycling of appendages in the adult, stem cell regulation, patterning, orientation, regional specificity and modulation by sex hormone nuclear receptors. I will also cover their roles in wound healing, hair regeneration and skin related diseases. It appears that Wnt signaling plays essential but distinct roles in different hierarchical levels of morphogenesis and organogenesis. Many of these areas have not yet been fully explored but are certainly promising areas of future research.The integument forms the interface between an organism and its environment. 1,2 As such it protects against dehydration, infection, temperature extremes, etc while providing a means for display, camouflage and other functions. 3 The skin can elaborate remarkable structural diversity producing specialized functions in a region-specific fashion to provide organisms with a selective advantage. For example, the development of feathers led to the acquisition of flight in birds and the formation of mammary glands enabled mammals to nurse their young. 4 The advantage of these evolutionary developments can be seen by the number of birds and mammals present today.Skin appendages, such as skin, hairs, feathers, scales, glands and teeth grow from the epithelium as a result of epithelial-mesenchymal interactions, 5 largely in response to common molecular signals with slight variations in their placement and timing during tissue morphogenesis. 6 Theoretically, stem cells are totipotent and progressively can be guided toward their specific fates by exposure to specific regulatory signals. The juxtaposition of molecular signals or lack thereof may have a tremendous impact on cell fate decisions. Hence, the difference between skin appendages is due to the topological arrangement of the epithelia during developmental processes. These are presumably regulated by adhesion molecules whose expression is controlled by signaling molecules as well as by physical constraints.Hairs and feathers are attractive model systems for experimental research because of their ability for seasonal or periodic renewal. Obviously not all hairs or feathers are replaced at one time or birds would lose all of their feathers at once and fall from the sky in midflight; rather hairs and feathers are replaced over a period of time in a wave-like pattern. 7 Yet this cycling behavior enables thousands of entirely new organs to be regenerated again and again throughout these animal's lives. Hairs and feathers demonstrate an incredible diversity of forms arising in different locations over the bod...

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Section: Adult Stem Cellsmentioning

confidence: 99%

Wnt signaling in skin organogenesis

Widelitz

2008

Organogenesis

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“…The molecular basis of GS was first described in 2007, when it was reported that GS is caused by loss‐of‐function mutations in the PORCN gene 3, 4…”

Section: Introductionmentioning

confidence: 99%

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

Frisk

Grandpeix-Guyodo

Silwerfeldt

et al. 2018

Clinical Case Reports

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“…The trait is caused by loss-of-function mutations in the X-linked PORCN gene (MIM# 300651) coding for a putative O-acyltransferase, a critical factor for the maturation of Wnt signaling molecules (Grzeschik et al, 2007;Wang et al, 2007). The human PORCN gene belongs to the evolutionarily conserved porcupine (Porc) gene family encoding endoplasmic reticulum proteins with multiple transmembrane domains putatively serving as Oacyltransferases.…”

Section: Introductionmentioning

confidence: 99%

PORCNmutations in focal dermal hypoplasia: coping with lethality

et al. 2009

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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.

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Deficiency of PORCN, a regulator of Wnt signaling, is associated with focal dermal hypoplasia

Cited by 257 publications

References 13 publications

Wnt signaling in skin organogenesis

Wnt signaling in skin organogenesis

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

PORCNmutations in focal dermal hypoplasia: coping with lethality

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