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The acral peeling skin syndrome (APSS) is a rare autosomal recessive disorder clinically characterized by asymptomatic desquamation of the skin limited to the hands and feet and histologically by cleavage at the stratum granulosum and stratum corneum level [Kiritsi et al.: J Invest Dermatol 2010;130:1741-1746]. We report on a 10-month-old boy with...
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... Our patient is one of the few adult-onset cases ever reported, confirming suggestions that the onset of clinical presentation may be variable. 4,9,17,18 and corticosteroids seem to be ineffective. 16 Considering the current lack of an effective treatment, genetic counselling is mandatory, as this promotes patient understanding of the condition and helps patients cope. ...
... The mutation (G113C) thus, affects the secondary and tertiary structure and interaction of TGM5 with IVL. It has been noticed that heat and humidity increases the symptomatic effect of TGM5 mutation[27]. With increase in temperature, the flexibility and fluidity of proteins have been found to increase[28]. ...
Objective: Acral peeling skin syndrome (APSS), a rare genetic disorder, indicated by the continuous blistering and shedding of the outer epidermal layers. Transglutaminase 5 (TGM5), a calcium-dependent TGM, present in the epidermis has been implicated as the cause of APSS. An attempt has been made to compare in silico the wild and mutant form of TGM5 and its implication on its interaction with involucrin (IVL). Methods: Comparative modeling was performed using MAESTRO for proteins TGM5 and IVL using templates from the protein databank. Generated model was later refined using side chain refinement and loop refinement. Three-dimensional (3D) structure of TGM5 and IVL was analyzed in PROCHECK, VERIFY3D, and ERRAT was used to assess the reliability of the 3D model. IMPACT package from Schrödinger was used to generate a binding site for calcium ion which is essential for functioning of protein. Energy minimization for the modelled structures was performed using IMPACT module of Schrodinger. Subsequently, wild type and mutated models of TGM5 was used for performing docking studies with IVL. Results: The structures for TGM5 and IVL were modeled and energy minimized using Schrödinger suite. Conserved calcium binding domain formed by three asparagine residues (N224, N226 and N229) and alanine (A221) corresponding to TGM3 was found in TGM5 at positions 226, 229, 231, and 234. Identification of probable active site for TGM5 was predicted using SiteMap program in Schrödinger. 17 cysteine residues are present in wild type structure of TGM5 and in mutated form G113C, the probability of forming an extra disulfide increases. With the mutation occurring at 113 position formation of disulfide bond between C113 and Cys306 increases manifold. This hypothesis was confirmed by the fact that root-mean-square distance value of energy minimized mutated TGM5 when compared to native TGM5 on aligning all 561 atoms was found to be 0.141 indicating a change of overall structure of protein. Conclusion: The mutation G113C is increasing the dynamic nature of the protein to increase as the probability of the formation of disulfide bond increases.
... This finding is consistent with our previous results showing that Dsg2 enhances cell proliferation. CSTA has been shown to possess antiapoptotic activity [31], is upregulated in several epithelial-derived malignancies including SCC [32], and is mutated in inherited cell-cell adhesion defective epidermal disorders [17][18][19]. Furthermore, CSTA inhibits cathepsins [33,34], which are also deregulated in skin cancer [35][36][37]. ...
Cell-cell adhesion is paramount in providing and maintaining multicellular structure and signal transmission between cells. In the skin, disruption to desmosomal regulated intercellular connectivity may lead to disorders of keratinization and hyperproliferative disease including cancer. Recently we showed transgenic mice overexpressing desmoglein 2 (Dsg2) in the epidermis develop hyperplasia. Following microarray and gene network analysis, we demonstrate that Dsg2 caused a profound change in the transcriptome of keratinocytes in vivo and altered a number of genes important in epithelial dysplasia including: calcium-binding proteins (S100A8 and S100A9), members of the cyclin protein family, and the cysteine protease inhibitor cystatin A (CSTA). CSTA is deregulated in several skin cancers, including squamous cell carcinomas (SCC) and loss of function mutations lead to recessive skin fragility disorders. The microarray results were confirmed by qPCR, immunoblotting, and immunohistochemistry. CSTA was detected at high level throughout the newborn mouse epidermis but dramatically decreased with development and was detected predominantly in the differentiated layers. In human keratinocytes, knockdown of Dsg2 by siRNA or shRNA reduced CSTA expression. Furthermore, siRNA knockdown of CSTA resulted in cytoplasmic localization of Dsg2, perturbed cytokeratin 14 staining and reduced levels of desmoplakin in response to mechanical stretching. Both knockdown of either Dsg2 or CSTA induced loss of cell adhesion in a dispase-based assay and the effect was synergistic. Our findings here offer a novel pathway of CSTA regulation involving Dsg2 and a potential crosstalk between Dsg2 and CSTA that modulates cell adhesion. These results further support the recent human genetic findings that loss of function mutations in the CSTA gene result in skin fragility due to impaired cell-cell adhesion: autosomal-recessive exfoliative ichthyosis or acral peeling skin syndrome.
... Acral peeling skin syndrome is a clinical variant of the rare, genetic, and recurrent exfoliative dermatosis known as peeling skin syndrome. It is an autosomal recessive disorder in which, unlike the generalized form, skin peeling is limited to the hands and feet [1,2]. The overwhelming majority of reported cases started manifesting clinically from early childhood and occurred in singleton patients. ...
... All variants are autosomal recessive and a detailed family history of skin exfoliation is therefore crucial. Depending on type, mutations in the CDSN or TGM5 or CSTA genes are implicated [1]. These genes play roles in the adhesive interactions between corneocytes and their mutation results in cleavage of the stratum corneum from the stratum granulosum, a phenomenon that explains the skin exfoliation. ...
... Most cases of acral peeling skin syndrome manifest in early childhood [1] and our patient is one of the few adult-onset cases ever reported, confirming suggestions that the onset of clinical presentation may be variable [5,9,11]. ...
Background:
Acral peeling skin syndrome is a rare autosomal recessive disorder in which skin exfoliation is limited to the hands and feet. While it typically manifests from early childhood, in this first reported case from South Africa, the patient did not manifest clinically until the fourth decade of life.
Case report:
A 44-year-old woman of African descent, 1 of a set of non-identical twins, presented with recurrent episodes of skin peeling of the upper and lower limbs. The first episode occurred 4 years prior, followed by perennial skin peeling during the spring seasons. She was not on treatment for any chronic disease and reported no exposure to chemicals or other irritants. The family, including the non-identical twin sister, has no history of skin disorders and the patient's HIV antibody test was negative. At presentation, physical examination revealed ongoing exfoliation with new skin formation on the palms and soles. The mucous membranes and nails were spared. Other systems were normal. Skin biopsy taken from the palms confirmed peeling skin syndrome. The patient was managed with topical aqueous cream and analgesics. She was briefly counseled on the nature and prognosis of the disease, and referred for genetic testing and counseling. On follow-up, she continues to have skin peeling once or twice a year.
Conclusions:
This first reported case of this rare disease in South Africa contributes to the growing body of literature on the disease and highlights the need for clinicians to be aware of its variable clinical onset.
Acral peeling skin syndrome (APSS, MIM #609796) is a rare autosomal recessive disorder characterized by superficial exfoliation and blistering of the volar and dorsal aspects of hands and feet. The level of separation is at the junction of the stratum granulosum and stratum corneum. APSS is caused by mutations in the TGM5 gene encoding transglutaminase-5, which is important for structural integrity of the outermost epidermal layers. The majority of patients originate from Europe and carry a p.(Gly113Cys) mutation in TGM5. In this study we report both European and non-European families carrying other mutations in the TGM5 gene. In 5 patients we found 3 novel mutations: c.1001+2_1001+3del, c.1171G>A and c.1498C>T. To confirm their pathogenicity we performed functional analyses with a transglutaminase activity assay, determined alternative splicing by reverse transcribed-PCR analysis and used databases and in silico prediction tools. This article is protected by copyright. All rights reserved.
This article is protected by copyright. All rights reserved.
Background
Acral peeling skin syndrome (APSS) is a rare skin fragility disorder usually caused by mutations in the transglutaminase 5 gene (TGM5).Methods
We investigated the mutation spectrum of APSS in United Kingdom, Germany and Poland.ResultsWe identified 59 children with APSS from 52 families. The phenotype was readily recognisable, with some variation in severity both within and between families. Most cases had been misdiagnosed as the localised form of epidermolysis bullosa simplex (EBS-loc). Eighteen different TGM5 mutations were identified, 15 of which were novel. Eight mutations were unique to a single family, nine each occurred in two families, while the common p.Gly113Cys mutation linked to a second missense variant p.Thr109Met occurred in 47 of the 52 families and was homozygous in 28. Most patients were of non-consanguineous Caucasian European origin.Conclusions
We propose that APSS is under-reported and widely misdiagnosed as EBS-loc, with significant counselling implications as APSS is autosomal recessive while EBS-loc is dominant. We recommend screening for TGM5 mutations when EBS-loc is suspected but not confirmed by mutations in KRT5 or KRT14. Our report trebles the number of known TGM5 mutations. It provides further evidence that p.Gly113Cys is a founder mutation in the European population. This is consistent with the striking ethnic distribution of APSS in UK, where the majority of patients are of non-consanguineous Caucasian European origin, in contrast to the pattern of other recessive skin disorders.This article is protected by copyright. All rights reserved.
