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Diagram illustrating the predicted consequences caused by three splice site mutations in the DSG1 (A) c.Ivs4-2A>G. (B) c.515C>T. (C) c.Ivs9-3C>G. Mutations are colored in red. Asterisks indicate premature termination codons.
Source publication
Striate palmoplantar keratoderma (SPPK; OMIM #148700) is a rare autosomal dominant genodermatosis characterized by linear hyperkeratosis on the digits and hyperkeratosis on the palms and soles. SPPK is known to be caused by heterozygous mutations in either the desmoglein 1 (DSG1), desmoplakin (DSP), or keratin 1 (KRT1) genes.
To define the molecula...
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Context 1
... novel mutation c.Ivs4-2A>G in Family 2 occurred in 3'-end of intron 4 of the DSG1 gene (Fig. 3B). Computational splice site analysis suggested that a novel potential splice acceptor site could be generated 1 bp upstream of the intron 4 -exon 5 junction (Fig. 4A). Thus, the mutation c.Ivs4-2A>G is predicted to cause abnormal splicing of exon 5, leading to a frameshift and a premature termination codon (PTC) in exon 5 (Fig. ...
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... the DSG1 gene (Fig. 3B). Computational splice site analysis suggested that a novel potential splice acceptor site could be generated 1 bp upstream of the intron 4 -exon 5 junction (Fig. 4A). Thus, the mutation c.Ivs4-2A>G is predicted to cause abnormal splicing of exon 5, leading to a frameshift and a premature termination codon (PTC) in exon 5 (Fig. ...
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... the exon 5 -intron 5 junction (Fig. 3D). Although it could result in an amino acid change from alanine to valine at codon 172, computational analysis suggested that the c.515C>T mutation could generate a putative splice donor site at the mutation site, which is predicted to cause an aberrant splicing of exon 5, resulting in a frameshift and a PTC (Fig. 4B). It is well known that a point mutation near the ends of an exon can affect splicing [18]. Furthermore, most DSG1 mutations identified to date result in a PTC [2 13 14 15], which supports our interpretation that the c.515C>T is most likely to function as a splice site mutation, rather than a missense ...
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... in the DSG1 gene in Family 4 (Fig. 3F). Computational splice site analysis indicated that the mutation would severely disrupt the splice acceptor sequence in intron 9, and instead, a putative splice acceptor site might be generated 2 bp upstream of the intron 9 -exon 10 junction, which is predicted to cause an abnormal splicing of exon 10 (Fig. 4C). Alternatively, the out-of-frame skipping of exon 10 (140 bp in size), might be another possible consequence caused by the mutation. Both possibilities would lead to a frameshift and a downstream ...
Context 5
... novel mutation c.Ivs4-2A>G in Family 2 occurred in 3'-end of intron 4 of the DSG1 gene (Fig. 3B). Computational splice site analysis suggested that a novel potential splice acceptor site could be generated 1 bp upstream of the intron 4 -exon 5 junction (Fig. 4A). Thus, the mutation c.Ivs4-2A>G is predicted to cause abnormal splicing of exon 5, leading to a frameshift and a premature termination codon (PTC) in exon 5 (Fig. ...
Context 6
... the DSG1 gene (Fig. 3B). Computational splice site analysis suggested that a novel potential splice acceptor site could be generated 1 bp upstream of the intron 4 -exon 5 junction (Fig. 4A). Thus, the mutation c.Ivs4-2A>G is predicted to cause abnormal splicing of exon 5, leading to a frameshift and a premature termination codon (PTC) in exon 5 (Fig. ...
Context 7
... the exon 5 -intron 5 junction (Fig. 3D). Although it could result in an amino acid change from alanine to valine at codon 172, computational analysis suggested that the c.515C>T mutation could generate a putative splice donor site at the mutation site, which is predicted to cause an aberrant splicing of exon 5, resulting in a frameshift and a PTC (Fig. 4B). It is well known that a point mutation near the ends of an exon can affect splicing [18]. Furthermore, most DSG1 mutations identified to date result in a PTC [2 13 14 15], which supports our interpretation that the c.515C>T is most likely to function as a splice site mutation, rather than a missense ...
Context 8
... in the DSG1 gene in Family 4 (Fig. 3F). Computational splice site analysis indicated that the mutation would severely disrupt the splice acceptor sequence in intron 9, and instead, a putative splice acceptor site might be generated 2 bp upstream of the intron 9 -exon 10 junction, which is predicted to cause an abnormal splicing of exon 10 (Fig. 4C). Alternatively, the out-of-frame skipping of exon 10 (140 bp in size), might be another possible consequence caused by the mutation. Both possibilities would lead to a frameshift and a downstream ...
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A 24-year-old man presented with linear hyperkeratotic plaques on the volar f ingers, which he had since childhood. That was exacerbated by manual labour. No family member was affected with similar condition. Histopathologic and electron microscopic results were consistent with striate palmoplantar keratoderma. Striate palmoplantar keratoderma or B...
Citations
... Its expression gradually increases throughout differentiation, reaching its highest level in the outer living layers of the epidermis . Dsg1 distribution is critical, in turn, for patterning ErbB family signaling pathways in the epidermis; it inhibits EGFR/MAPK signaling during early differentiation and promotes ErbB2-mediated tight junction barrier formation during late differentiation (Broussard et al., 2021;Getsios et al., 2009; and pemphigus foliaceus (PF) (Cheng et al., 2016;Dua-Awereh et al., 2009;Has et al., 2015;Hershkovitz et al., 2009;Samuelov et al., 2013;Schmidt et al., 2019). ...
... It does so by remodeling cortical actin to redistribute membrane tension in basal cells . This redistribution is required for releasing basal cells from the basement membrane for transit into the suprabasal layers, a process called delamination that contributes to the formation and maintenance of the regenerating multi-layered epidermis (Damen et al., 2021;Miroshnikova et al., 2018;Nekrasova et al., 2018;Watt and Green, 1982;Williams et al., 2014). Dsg1's role in this process requires its proper localization on the plasma membrane, in detergent insoluble regions segregated from the AJ protein, E-cadherin . ...
... doi: bioRxiv preprint delamination . Delamination is an important contributor to the process of stratification in conjunction with the asymmetric division of basal cells to establish and maintain the epidermal layer (Damen et al., 2021;Nekrasova et al., 2018;Williams et al., 2014). The dynein light chain Tctex-1 was also found to be necessary for Dsg1's proper localization on the insoluble plasma membrane, segregated from E-cadherin . ...
Sorting and trafficking transmembrane cargo is essential for tissue development and homeostasis. However, the importance of intracellular trafficking in the development and regeneration of stratified epidermis has not been investigated. Here we identify the interaction between VPS35, an essential component of the retromer endosomal trafficking complex, and the desmosomal cadherin, Desmoglein 1 (Dsg1). Dsg1 is specifically expressed in stratified tissues and when properly localized on the plasma membrane, promotes epidermal stratification. We show that the retromer drives Dsg1 recycling from the endolysosomal system to the plasma membrane to support keratinocyte stratification and differentiation. The retromer enhancing chaperone, R55 promotes the plasma membrane localization of Dsg1 and a Dsg1 mutant associated with Severe dermatitis, multiple Allergies, and Metabolic wasting (SAM) syndrome, enhancing the ability of SAM-Dsg1 to promote stratification. Our work provides the first evidence for retromer function in epidermal regeneration and identifies it as a potential therapeutic skin disease target.
... In 1999, a heterozygous DSG1 mutation was identified in a family with striate palmoplantar keratoderma (SPPK1; MIM 148700). 8 SPPK1 is an autosomal dominant disorder characterised by linear hyperkeratotic bands on the fingers and palms alongside focal keratoderma of the soles, [9][10][11][12][13][14] with histological findings of orthohyperkeratosis, papillomatosis, keratinocyte dyshesion and widened intercellular spaces. 15 Skin blistering has been reported in certain DSG1-haploinsufficient individuals but is not a feature in most. ...
The desmosome is a type of intercellular junction found in epithelial cells, cardiomyocytes and other specialised cell types. Composed of a network of transmembranous cadherins and intracellular armadillo, plakin and other proteins, desmosomes contribute to cell‐cell adhesion, signalling, development and differentiation. Mutations in genes encoding desmosomal proteins result in a spectrum of erosive skin and mucosal phenotypes that also may affect hair or heart. This review summarises the molecular pathology and phenotypes associated with desmosomal dysfunction with a focus on inherited disorders that involve the skin/hair as well as associated extracutaneous pathologies. We reviewed the relevant literature to collate studies of pathogenic human mutations in desmosomes that have been reported over the last 25 years. Mutations in 12 different desmosome genes have been documented with mutations in 9 genes affecting the skin/mucous membranes (DSG1, DSG3, DSC2, DSC3, JUP, PKP1, DSP, CDSN, PERP) and 8 resulting in hair abnormalities (DSG4, DSC2, DSC3, JUP, PKP1, DSP, CDSN, PERP). Mutations in 3 genes can result in cardio‐cutaneous syndromes (DSC2, JUP, DSP) although mutations have been described in 5 genes in inherited heart disorders that may lack any dermatological manifestations (DSG2, DSC2, JUP, PKP2, DSP). Understanding the diverse nature of these clinical phenotypes as well as the desmosome gene mutation(s) has clinical value in managing and counselling patients, as well as demonstrating the biological role and activity of specific components of desmosomes in skin and other tissues.
... Nagashima PPK is caused by biallelic loss of function mutation in SERPINB7 while, MDM is caused by SLURP1 gene mutation [20]. Therefore, MDM is genetically distinct from Nagashima PPK [32]. PPKs are diagnosed on the basis of differential diagnosis to find out the ...
Abstract
Background
Inherited palmoplantar keratodermas (PPKs) are clinically and genetically heterogeneous and phenotypically diverse group of genodermatoses characterized by hyperkeratosis of the palms and soles. More than 20 genes have been reported to be associated with PPKs including desmoglein 1 (DSG1) a key molecular component for epidermal adhesion and differentiation. Mal de Meleda (MDM) is a rare inherited autosomal recessive genodermatosis characterized by transgrediens PPK, associated with mutations in the secreted LY6/PLAUR domain containing 1 (SLURP1) gene.
Methods
This study describes clinical as well as genetic whole exome sequencing (WES) and di-deoxy sequencing investigations in two Pakistani families with a total of 12 individuals affected by PPK.
Results
WES identified a novel homozygous nonsense variant in SLURP1, and a novel heterozygous nonsense variant in DSG1, as likely causes of the conditions in each family.
Conclusions
This study expands knowledge regarding the molecular basis of PPK, providing important information to aid clinical management in families with PPK from Pakistan.
... Nagashima PPK is caused by biallelic loss of function mutation in SERPINB7 while, MDM is caused by SLURP1 gene mutation [20]. Therefore, MDM is genetically distinct from Nagashima PPK [32]. PPKs are diagnosed on the basis of differential diagnosis to find out the Table 2. ...
Background:
Inherited palmoplantar keratodermas (PPKs) are clinically and genetically heterogeneous and phenotypically diverse group of genodermatoses characterized by hyperkeratosis of the palms and soles. More than 20 genes have been reported to be associated with PPKs including desmoglein 1 (DSG1) a key molecular component for epidermal adhesion and differentiation. Mal de Meleda (MDM) is a rare inherited autosomal recessive genodermatosis characterized by transgrediens PPK, associated with mutations in the secreted LY6/PLAUR domain containing 1 (SLURP1) gene.
Methods:
This study describes clinical as well as genetic whole exome sequencing (WES) and di-deoxy sequencing investigations in two Pakistani families with a total of 12 individuals affected by PPK.
Results:
WES identified a novel homozygous nonsense variant in SLURP1, and a novel heterozygous nonsense variant in DSG1, as likely causes of the conditions in each family.
Conclusions:
This study expands knowledge regarding the molecular basis of PPK, providing important information to aid clinical management in families with PPK from Pakistan.
... This has been observed for most of the DSG1 mutations associated with SPPK. In fact, among the 27 mutations detected currently (11 frameshift, nine nonsense, five splice site, and two missense) (Lovgren et al., 2017;Vodo et al., 2018), 26 are predicted to result in a PTC (Hershkovitz, Lugassy, Indelman, Bergman, & Sprecher, 2009;Lovgren et al., 2017), and for all of them the pathological effects have been associated with haploinsufficiency of DSG1 protein (Dua-Awereh, Shimomura, Kraemer, Wajid, & Christiano, 2009;Lovgren et al., 2017). In addition, our study suggests a phenotypic variability for mutations located in the DSG1 gene. ...
Palmoplantar keratoderma (PPK) is a heterogenous group of skin disorders characterized by a persistent thickening of the palms of the hands and sometimes soles of the feet. PPK can be classified into many types, including diffuse, transgradient, and focal or striate, where the areas of palmoplantar skin are alternatively thickened. Mutations in four main genes, keratin 9 (KRT9), keratin 1 (KRT1), desmoglein (DSG1), and desmoplakin (DSP), have been associated with PPK. Striate PPK (SPPK) is commonly caused by mutations in DSG1. However, DSP and KRT1 gene mutations have been identified in some cases. In this study, fragment and sequencing analysis were performed for a large Syrian family with dominant SPPK. Segregation analysis showed a linkage with DSG1 gene. Direct Sanger sequencing identified a new mutation c.dup165_168AGCA. This frameshift mutation was heterozygous in all affected family members and absent in all normal individuals.
... 7 Desmoglein 1 haploinsufficiency has been known for many years to cause autosomal dominant striate palmoplantar keratoderma. [8][9][10][11][12][13][14] In the mother of our patient, the heterozygous mutation p.R887* led only to minor focal keratoses of the soles. Recently, homozygous loss-of-function mutations were associated with a new disorder with severe dermatitis, multiple allergies and metabolic wasting in two families (Fig. 2b). 3 Compared with these patients, the present case displays phenotypic similarities, but also differences (Table S2, see Supporting Information). ...
Monoallelic desmoglein 1 mutations are known for many years to cause striate palmoplantar keratoderma, but only recently, biallelic loss-of-function mutations were associated with a new disorder, designated as SAM syndrome, comprising severe dermatitis, multiple allergies and metabolic wasting in two consanguineous families. We report on a new case from a third independent family with the homozygous nonsense mutation, c.2659C>T, p.R887* in exon 15 of DSG1. This mutation led to mRNA decay and loss of expression of desmoglein 1. The clinical phenotype consisted of severe palmoplantar keratoderma, dermatitis and multiple allergies. In contrast to the previous cases, malabsorbtion, hypoalbuminemia, developmental delay, hypotrichosis or severe recurrent infections were not observed.This article is protected by copyright. All rights reserved.
... These data led us to investigate the DSG1 C terminus as a potential scaffold for intracellular signaling events. A subset of patients with striate palmoplantar keratoderma (SPPK) are DSG1 deficient, with keratinization defects resembling, to an extent, cutaneous symptoms associated with RASopathies (2,6,7,(15)(16)(17)(18). That these genetic disorders often arise from mutations in ancillary regulators of MAPK signaling highlights the importance of identifying proteins that provide the physical link between DSG1 cytoplasmic domains and the core MAPK machinery. ...
Genetic disorders of the Ras/MAPK pathway, termed RASopathies, produce numerous abnormalities, including cutaneous keratodermas. The desmosomal cadherin, desmoglein-1 (DSG1), promotes keratinocyte differentiation by attenuating MAPK/ERK signaling and is linked to striate palmoplantar keratoderma (SPPK). This raises the possibility that cutaneous defects associated with SPPK and RASopathies share certain molecular faults. To identify intermediates responsible for executing the inhibition of ERK by DSG1, we conducted a yeast 2-hybrid screen. The screen revealed that Erbin (also known as ERBB2IP), a known ERK regulator, binds DSG1. Erbin silencing disrupted keratinocyte differentiation in culture, mimicking aspects of DSG1 deficiency. Furthermore, ERK inhibition and the induction of differentiation markers by DSG1 required both Erbin and DSG1 domains that participate in binding Erbin. Erbin blocks ERK signaling by interacting with and disrupting Ras-Raf scaffolds mediated by SHOC2, a protein genetically linked to the RASopathy, Noonan-like syndrome with loose anagen hair (NS/LAH). DSG1 overexpression enhanced this inhibitory function, increasing Erbin-SHOC2 interactions and decreasing Ras-SHOC2 interactions. Conversely, analysis of epidermis from DSG1-deficient patients with SPPK demonstrated increased Ras-SHOC2 colocalization and decreased Erbin-SHOC2 colocalization, offering a possible explanation for the observed epidermal defects. These findings suggest a mechanism by which DSG1 and Erbin cooperate to repress MAPK signaling and promote keratinocyte differentiation.
... 19 More than 16 different heterozygous mutations have been identified in DSG1, most of them resulting in the introduction of a premature stop codon. 22,23 Ultrastructural analysis has shown that the palmar skin of SPPK patients contains very few desmosomes, and that those present in 365 Cadherins in Inherited Human Disorders the suprabasal layers are abnormally small and poorly formed. 24 Diverse mutations of DSG4 (intragenic deletions, missense and null mutations) have been reported in two autosomal recessive human hair disorders with overlapping clinical features: localized autosomal recessive hypotrichosis (LAH; OMIM 607903) 20,25 and the autosomal recessive monilethrix-like form (OMIM 607903). ...
The tight control of cell-cell connectivity mediated by cadherins is a key issue in human health and disease. The human genome contains over 115 genes encoding cadherins and cadherin-like proteins. Defects in about 21 of these proteins (8 classical, 5 desmosomal, 8 atypical cadherins) have been linked to inherited disorders in humans, including skin and hair disorders, cardiomyopathies, sensory defects associated with deafness and blindness, and psychiatric disorders. With the advent of exome and genome sequencing techniques, we can anticipate the discovery of yet more evidence for the involvement of additional cadherins. Elucidation of the related physiopathological mechanisms underlying these conditions should help to clarify the roles played by these cadherins in tissues and the ways in which defects in different cadherins cause such a wide spectrum of associated phenotypes. These disorders also constitute disparate model systems for investigations of the relative contributions of mechanical adhesive strength and intracellular signaling pathways to the pathogenic process for a given cadherin.
... More likely, haploinsufficiency of KRT74 is the predominant mechanism underlying woolly hair in the family. Mutations in desmoglein-1 (Dua-Awereh et al. 2009) and keratin-5 (Betz et al. 2006) causing palmoplantar keratoderma and Dowling-Degos disease, respectively, have been predicted to result from haploinsufficiency of the two genes. The missense mutation (p.Asp482Asn) identified in the present family B resides in the tail domain of K74 protein. ...
Autosomal dominant woolly hair (ADWH) is an inherited condition of tightly curled and twisted scalp hair. Recently, a mutation in human keratin-74 (KRT74) gene has been shown to cause this form of hereditary hair disorder. In the present study, we have described two families (A and B) having multiple individuals affected with autosomal dominant form of hair loss disorders. In family A, 10 individuals showed ADWH phenotype while in the family B, 14 individuals showed hypotrichosis of the scalp. Genotyping using polymorphic microsatellite markers showed linkage of both the families to type II keratin gene cluster on the chromosome 12q12-14.1. Mutation analysis of the KRT74 gene identified two novel mutations in the affected individuals of the families. The sequence analysis revealed a splice acceptor site mutation (c.IVS8-1G>A) in family A and a missense variant (c.1444G>A, p.Asp482Asn) in family B. Mutations identified in the present study extend the body of evidence implicating the KRT74 gene in the pathogenesis of autosomal dominant hair loss disorders.
... A number of pathogenic splice site and frameshift DSG1 mutations, believed to cause haploinsufficiency, cause SPPK (OMIM 148700) [120][121][122][123]. The patients' skin exhibits fewer, smaller, desmosomes and loss of IF attachment. ...
Desmosomes are intercellular junctions whose primary function is strong intercellular adhesion, known as hyperadhesion. In the present review, we discuss how their structure appears to support this function as well as how they are assembled and down-regulated. Desmosomal components also have signalling functions that are important in tissue development and remodelling. Their adhesive and signalling functions are both compromised in genetic and autoimmune diseases that affect the heart, skin and mucous membranes. We conclude that much work is required on structure-function relationships within desmosomes in vivo and on how they participate in signalling processes to enhance our knowledge of tissue homoeostasis and human disease.
