A Plakophilin-1 Gene Mutation in an Egyptian Family with Ectodermal Dysplasia-Skin Fragility Syndrome

Abdalla, Ebtesam; Has, Cristina

doi:10.1159/000369267

Cited by 5 publications

(2 citation statements)

References 12 publications

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“…Several features of the PKP1 e/e mice closely resemble the phenotype of patients with PKP1 mutations causing EDSFS (OMIM 604536). Prevalence of EDSFS is unknown, because only a few patients carrying a variety of different mutations have been reported (Abdalla and Has, 2014;McGrath and Mellerio, 2010;Sprecher et al, 2004). Notably, most PKP1 mutations lie in splice donor or acceptor sites, which may result in exon skipping or cryptic splicing rather than complete ablation of the protein (McGrath and Mellerio, 2010;Sprecher et al, 2004).…”

Section: Discussionmentioning

confidence: 99%

Growth Retardation, Loss of Desmosomal Adhesion, and Impaired Tight Junction Function Identify a Unique Role of Plakophilin 1 In Vivo

Rietscher

Wolf

Hause

et al. 2016

Journal of Investigative Dermatology

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Desmosomes mediate strong intercellular adhesion through desmosomal cadherins that interact with intracellular linker proteins including plakophilins (PKPs) 1-3 to anchor the intermediate filaments. PKPs show overlapping but distinct expression patterns in the epidermis. So far, the contribution of individual PKPs in differentially regulating desmosome function is incompletely understood. To resolve the role of PKP1 we ablated the PKP1 gene. Here, we report that PKP1(-/-) mice were born at the expected mendelian ratio with reduced birth weight, but they otherwise appeared normal immediately after birth. However, their condition rapidly declined, and the mice died within 24 hours, developing fragile skin with lesions in the absence of obvious mechanical trauma. This was accompanied by sparse and small desmosomes. Newborn PKP1(-/-) mice showed disturbed tight junctions with an impaired inside-out barrier, whereas the outside-in barrier was unaffected. Keratinocytes isolated from these mice showed strongly reduced intercellular cohesion, delayed tight junction formation, and reduced transepithelial resistance and reduced proliferation rates. Our study shows a nonredundant and essential role of PKP1 in desmosome and tight junction function and supports a role of PKP1 in growth control, a function that is crucial in wound healing and epidermal carcinogenesis.

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Section: Discussionmentioning

confidence: 99%

Growth Retardation, Loss of Desmosomal Adhesion, and Impaired Tight Junction Function Identify a Unique Role of Plakophilin 1 In Vivo

Rietscher

Wolf

Hause

et al. 2016

Journal of Investigative Dermatology

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“…We identified 16 individual cases of EDSF syndrome caused by bi‐allelic PKP1 germline mutations and 1 case caused by postzygotic mosaicism; we also include two further cases that are reported in this article (Tables 1 and 2). [ 10,12‐25 ] Consanguinity was present in 68.8% of the cases (11/16; not reported in 2 cases). None of the heterozygous carrier parents reported any skin or ectodermal abnormalities.…”

Section: Resultsmentioning

confidence: 99%

Ectodermal dysplasia‐skin fragility syndrome: Two new cases and review of this desmosomal genodermatosis

Doolan

Gomaa

Fawzy

et al. 2020

Experimental Dermatology

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Background: Desmosomes are intercellular cadherin-mediated adhesion complexes that anchor intermediate filaments to the cell membrane and are required for strong adhesion for tissues under mechanical stress. One specific component of desmosomes is plakophilin 1 (PKP1), which is mainly expressed in the spinous layer of the epidermis. Loss-of-function autosomal recessive mutations in PKP1 result in ectodermal dysplasia-skin fragility (EDSF) syndrome, the initial inherited Mendelian disorder of desmosomes first reported in 1997. Methods: To investigate two new cases of EDSF syndrome and to perform a literature review of pathogenic PKP1 mutations from 1997 to 2019. Results: Sanger sequencing of PKP1 identified two new homozygous frameshift mutations: c.409_410insAC (p.Thr137Thrfs*61) and c.1213delA (p.Arg411Glufs*22). Comprehensive analyses were performed for the 18 cases with confirmed bi-allelic PKP1 gene mutations, but not for one mosaic case or 6 additional cases that lacked gene mutation studies. All pathogenic germline mutations were loss-of-function (splice site, frameshift, nonsense) with mutations in the intron 1 consensus acceptor splice site (c.203-1>A or G>T) representing recurrent findings. Skin fragility and nail involvement were present in all affected individuals (18/18), with most cases showing palmoplantar keratoderma (16/18), alopecia/hypotrichosis (16/18) and perioral fissuring/cheilitis (12/15; not commented on in 3 cases). Further observations in some individuals included pruritus, failure to thrive with low height/weight centiles, follicular hyperkeratosis, hypohidrosis, walking difficulties, dysplastic dentition and recurrent chest infections. Conclusion: These data expand the molecular basis of EDSF syndrome and help define the spectrum of both the prototypic and variable manifestations of this desmosomal genodermatosis. K E Y W O R D S desmosome, ectodermal dysplasia-skin fragility syndrome, Plakophilin 1 | 521 DOOLAN et AL.

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Targeting Bone Metastases Signaling Pathway UsingMoringa oleiferaSeed Nutri-miRs: A Cross Kingdom Approach

Bhadresha

Patel

Brahmbhatt

et al. 2021

Nutrition and Cancer

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A Plakophilin-1 Gene Mutation in an Egyptian Family with Ectodermal Dysplasia-Skin Fragility Syndrome

Cited by 5 publications

References 12 publications

Growth Retardation, Loss of Desmosomal Adhesion, and Impaired Tight Junction Function Identify a Unique Role of Plakophilin 1 In Vivo

Growth Retardation, Loss of Desmosomal Adhesion, and Impaired Tight Junction Function Identify a Unique Role of Plakophilin 1 In Vivo

Ectodermal dysplasia‐skin fragility syndrome: Two new cases and review of this desmosomal genodermatosis

Targeting Bone Metastases Signaling Pathway UsingMoringa oleiferaSeed Nutri-miRs: A Cross Kingdom Approach

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