Peeling skin syndrome associated with novel variant in <i>FLG2</i> gene

Alfares, Ahmed; Al-Khenaizan, Sultan; Mutairi, Fuad Al

doi:10.1002/ajmg.a.38468

Cited by 13 publications

(14 citation statements)

References 9 publications

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“…In contrast with this body of circumstantial evidence, our and recent other data (Alfares et al, 2017; Bolling et al, 2018) suggest that filaggrin 2 also, and possibly mainly, contributes to cell-cell adhesion in the cornified layers rather than to epidermal barrier integrity only. In this regard, it is of interest to note that no permeability defect was found in skin equivalents downregulated for filaggrin 2 (Pendaries et al, 2015).…”

Section: Discussioncontrasting

confidence: 99%

“…The above results as well as other recent data (Alfares et al, 2017; Bolling et al, 2018) support the possibility that filaggrin 2 deficiency is the proximal cause of type A PSS that manifests with heat-induced superficial peeling (Levy and Goldsmith, 1982). To ascertain directly the effect of filaggrin 2 deficiency on CDSN, which is downregulated in the skin of the patients, as well as on the expression of other adhesion proteins, we stained primary keratinocytes silenced for FLG2 for CDSN, desmoglein 1, and E-cadherin.…”

Section: Mutational Analysissupporting

confidence: 87%

“…Two recent studies identified the same homozygous variant in FLG2 encoding filaggrin 2, which cosegregated with PSS3 (Alfares et al, 2017; Bolling et al, 2018). The functional significance of this variant has not been studied.…”

Section: Introductionmentioning

confidence: 95%

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Filaggrin 2 Deficiency Results in Abnormal Cell-Cell Adhesion in the Cornified Cell Layers and Causes Peeling Skin Syndrome Type A

Mohamad

Sarig

Godsel

et al. 2018

Journal of Investigative Dermatology

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Peeling skin syndromes form a large and heterogeneous group of inherited disorders characterized by superficial detachment of the epidermal cornified cell layers, often associated with inflammatory features. Here we report on a consanguineous family featuring noninflammatory peeling of the skin exacerbated by exposure to heat and mechanical stress. Whole exome sequencing revealed a homozygous nonsense mutation in FLG2, encoding filaggrin 2, which cosegregated with the disease phenotype in the family. The mutation was found to result in decreased FLG2 RNA levels as well as almost total absence of filaggrin 2 in the patient epidermis. Filaggrin 2 was found to be expressed throughout the cornified cell layers and to colocalize with corneodesmosin that plays a crucial role in maintaining cell-cell adhesion in this region of the epidermis. The absence of filaggrin 2 in the patient skin was associated with markedly decreased corneodesmosin expression, which may contribute to the peeling phenotype displayed by the patients. Accordingly, using the dispase dissociation assay, we showed that FLG2 downregulation interferes with keratinocyte cell-cell adhesion. Of particular interest, this effect was aggravated by temperature elevation, consistent with the clinical phenotype. Restoration of corneodesmosin levels by ectopic expression rescued cell-cell adhesion. Taken together, the present data suggest that filaggrin 2 is essential for normal cell-cell adhesion in the cornified cell layers.

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Section: Discussioncontrasting

confidence: 99%

Section: Mutational Analysissupporting

confidence: 87%

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Filaggrin 2 Deficiency Results in Abnormal Cell-Cell Adhesion in the Cornified Cell Layers and Causes Peeling Skin Syndrome Type A

Mohamad

Sarig

Godsel

et al. 2018

Journal of Investigative Dermatology

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“…The association between FLG2 loss-of-function variants and skin disorders has been reported previously. African-American children carrying common FLG2 variants p.Ser2377* (rs12568784, minor allele frequency of 0.29), p.His1249Arg (rs16833974, minor allele frequency of 0.24), p.Gln2053del224, minor allele frequency of 0.04), and p.Ser2392* (rs150529054, minor allele frequency of 0.01) were more likely to have persistent atopic dermatitis (Margolis et al, 2014a(Margolis et al, , 2014b, while the FLG2 variant p.Ser211* was identified in a consanguineous family with peeling skin disease (Alfares et al, 2017). Because FLG2 loss-of-function variants seem to occur in the population, even in a homozygous state, their pathogenicity had remained elusive.…”

mentioning

confidence: 99%

Peeling Skin Disorders: A Paradigm for Skin Desquamation

Has

2018

Journal of Investigative Dermatology

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Epidermal desquamation is the highly regulated process of invisible shedding of corneocytes from the outermost layers of the stratum corneum. This occurs through the interplay between proteases and their inhibitors that control the degradation of corneodesmosomes. Skin peeling refers to exaggerated visible superficial desquamation and can occur in inherited and acquired conditions. The illumination of the molecular basis of genetic disorders with skin peeling sheds light on the biological mechanisms of epidermal desquamation and skin barrier homeostasis. Proteins that are mutated in peeling skin disorders are components of corneodesmosomes (CDSN, DSG1) or protease inhibitors (LEKTI, CSTA, CAST, or SERPIN8). FLG2 emerged as a new player that regulates epidermal desquamation, as demonstrated by the phenotype observed in patients reported by 2 independent groups.

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“…ADGRV1 is one of the biallelic pathogenic identi cation markers of Usher syndrome 60 , which is characterized by congenital bilateral sensorineural hearing loss 61 . The de ciency of FLG2 causes defective adhesion between corni ed cells, which leads to peeling skin syndrome 62 . However, the roles of these two genes in cancer remain unclear, and further studies are required.…”

Section: Key Genes In the Gene Mutation Analysismentioning

confidence: 99%

Establishment of a prognostic model based on immune infiltration-related genes and clinical information in ovarian cancer

Kong¹,

Zhang²,

Gao³

et al. 2020

Preprint

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Background Ovarian cancer is one of the most lethal gynecological cancers,and is in the top five cancer types associated with death in women. Immune infiltration of ovarian cancer is a critical factor in determining patient's prognosis. In addition to immune infiltration, key mutations also have a greater impact on the development and prognosis of OV.Methods Using data from TCGA and GTEx database combined with WGCNA and ESTIMATE methods, genes related to OV occurrence and immune infiltration were identified. Lasso and multivariate Cox regression were applied to define a prognostic score (IGCI score) based on immune genes and clinical information. The IGCI score has been verified by K-M curves, ROC curves, C-index on test set. Based on mutation data from TCGA, we identified key mutations related to immune infiltration by Chi-squared tests and we also did survival analysis of these mutations.Results In this section, we found 46 genes related to disease occurrence and immune infiltration, IGCI score was established based on six factors: Age, White, Pharmaceutical, FGF7, CCR1 and CD14. In test set, IGCI score (C-index = 0.630) is significantly better than AJCC stage (C-index = 0.541, P < 0.05) and CIN25 (C-index = 0.571, P < 0.05). Chi-squared tests revealed that 6 mutations are significantly (P < 0.05) related to immune infiltration : BRCA1, ZNF462, VWF, RBAK, RB1, and ADGRV1. According to mutation survival analysis, we found another 5 key mutations significantly related to patient prognosis (P < 0.05): CSMD3, FLG2, HMCN1, TOP2A, TRRAP. RB1 and CSMD3 mutations had small p-value (P < 0.1) in both Chi-squared tests and survival analysis. Then we conducted a drug sensitivity analysis of key mutation and found when RB1 mutation occurs, the efficacy of six anti-tumor drugs has changed significantly (P < 0.05).Conclusion Based on immune-related genes and clinical information, we have established an ovarian cancer prognosis score that is superior to other methods. At the same time, RB1 and CSMD3 gene mutations are considered to be closely related to ovarian cancer immunity and prognosis.

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Peeling skin syndrome associated with novel variant in FLG2 gene

Cited by 13 publications

References 9 publications

Filaggrin 2 Deficiency Results in Abnormal Cell-Cell Adhesion in the Cornified Cell Layers and Causes Peeling Skin Syndrome Type A

Filaggrin 2 Deficiency Results in Abnormal Cell-Cell Adhesion in the Cornified Cell Layers and Causes Peeling Skin Syndrome Type A

Peeling Skin Disorders: A Paradigm for Skin Desquamation

Establishment of a prognostic model based on immune infiltration-related genes and clinical information in ovarian cancer

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