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Clinical features, histopathology and transmission electron microscopy of the proband. (A) Note extensive blistering on the right arm of the proband who also had bilateral cleft lip and cleft palate. (B) Light microscopy revealed non-inflammatory tissue separation at the dermal–epidermal junction (H & E, ×40). (C) Transmission electron microscopy of the dermal–epidermal junction revealed the presence of hemidesmosomes lacking the inner plaque (arrowheads), and segments of the basement membrane zone which were morphologically perturbed (arrows). (D) Intermediate filaments were severed from the lower portion of the basal keratinocytes and condensed perinuclearly (open arrow). There was vacuolization within the lower portion of the keratinocytes (*) and local herniation of the basal cells into the upper papillary dermis (arrows).
Source publication
Junctional epidermolysis bullosa with congenital pyloric or duodenal atresia is a distinct variant within this group of autosomal recessive blistering skin diseases. In this study we demonstrate, for the first time, a homozygous mutation in the alpha6 integrin gene (ITGA6) in a family with three affected individuals. For this purpose, we first dete...
Contexts in source publication
Context 1
... splicing involving exon 12 (19). If the aberrant splicing results in the skipping of the entire exon, which consists of 161 bp, this would be out-of-frame potentially resulting in a frameshift and prema- ture termination codon 3 bp downstream from the site of the mutation and predicting a protein truncated within the extracellu- lar domain (Fig. 3A). No RNA was available from the proband or his parents to test this possibility, however, screening of 124 unrelated control individuals using HphI restriction enzyme failed to reveal the presence of this nucleotide substitution, suggesting that it is pathogenetic in this ...
Context 2
... healthy girl. The proband was found by prenatal ultrasound examination to have bilateral cleft lip but no evidence of duodenal atresia was noted. The pregnancy was allowed to continue to term, and a baby boy was delivered with bilateral cleft lip and cleft palate ( Fig. 2A). On the third day of life, the child developed extensive blistering (Fig. 3A) and died at the age of 29 days. Histology of the proband's skin revealed blister formation at the dermal-epidermal junction (Fig. 3B). Trans- mission electron microscopy of the unaffected perilesional skin revealed abnormalities in hemidesmosomes ( Fig. 3C and D). Specifically, although numerous hemidesmosomes were present many of them ...
Context 3
... was noted. The pregnancy was allowed to continue to term, and a baby boy was delivered with bilateral cleft lip and cleft palate ( Fig. 2A). On the third day of life, the child developed extensive blistering (Fig. 3A) and died at the age of 29 days. Histology of the proband's skin revealed blister formation at the dermal-epidermal junction (Fig. 3B). Trans- mission electron microscopy of the unaffected perilesional skin revealed abnormalities in hemidesmosomes ( Fig. 3C and D). Specifically, although numerous hemidesmosomes were present many of them lacked both inner plaques and sub-basal dense plates (Fig. 3C). In several areas, the BMZ was seen to be highly disorganized and ...
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... palate ( Fig. 2A). On the third day of life, the child developed extensive blistering (Fig. 3A) and died at the age of 29 days. Histology of the proband's skin revealed blister formation at the dermal-epidermal junction (Fig. 3B). Trans- mission electron microscopy of the unaffected perilesional skin revealed abnormalities in hemidesmosomes ( Fig. 3C and D). Specifically, although numerous hemidesmosomes were present many of them lacked both inner plaques and sub-basal dense plates (Fig. 3C). In several areas, the BMZ was seen to be highly disorganized and there was apparent herniation of the basal cells into the papillary dermis. Finally, the association of keratin intermediate filaments ...
Context 5
... of the proband's skin revealed blister formation at the dermal-epidermal junction (Fig. 3B). Trans- mission electron microscopy of the unaffected perilesional skin revealed abnormalities in hemidesmosomes ( Fig. 3C and D). Specifically, although numerous hemidesmosomes were present many of them lacked both inner plaques and sub-basal dense plates (Fig. 3C). In several areas, the BMZ was seen to be highly disorganized and there was apparent herniation of the basal cells into the papillary dermis. Finally, the association of keratin intermediate filaments with hemidesmosomes was severed leading to perinuclear condensation of these filaments within the basal cells with apparent ...
Context 6
... was seen to be highly disorganized and there was apparent herniation of the basal cells into the papillary dermis. Finally, the association of keratin intermediate filaments with hemidesmosomes was severed leading to perinuclear condensation of these filaments within the basal cells with apparent vacuolization of the lower portion of the cells (Fig. 3C and D). These findings, together with the clinical association of JEB with duodenal atresia, were consistent with an α6β4 integrin defect (13,26,27), but unfortunately immunohisto- chemistry was not performed before the demise of the ...
Citations
... It has been proposed that itga6, itga3, and itga7 might have a common ancestor [27,28]; however, ITGA6 is encoded by the itga6 gene located in chromosome 2 (2q31.1) [29], and its expression is regulated at multiple layers. Multiple transcription factors, including MYC, RUNX1, HIFs, and FOSL1, bind to the itga6 promoter region and enhance its transcription [8,28,[30][31][32] (Figure 1A). ...
Simple Summary
Integrins play key roles in mediating cell adhesion and delivering chemical and mechanical signals to the interior of the cell. Consequently, they actively control cellular proliferation, differentiation, and apoptosis. Integrin signaling dysregulation can be a major factor in the development of tumors, and it is involved in the processes of the malignant plasticity of the epithelium, the reactivation of metastasis, and resistance to therapeutic interventions. Here, we describe the current understanding of the α6-integrin subunit (ITGA6, also known as CD49f and/or VLA6; encoded by the gene itga6) in cancer cells. The roles of ITGA6 in cell adhesion, stemness, metastasis, angiogenesis, and drug resistance, and as a diagnostic biomarker, are discussed. The importance of ITGA6 in the progression of a number of cancers, including hematological malignancies, suggests its potential usage as a novel therapeutic target.
Abstract
Over the past decades, our knowledge of integrins has evolved from being understood as simple cell surface adhesion molecules to receptors that have a complex range of intracellular and extracellular functions, such as delivering chemical and mechanical signals to cells. Consequently, they actively control cellular proliferation, differentiation, and apoptosis. Dysregulation of integrin signaling is a major factor in the development and progression of many tumors. Many reviews have covered the broader integrin family in molecular and cellular studies and its roles in diseases. Nevertheless, further understanding of the mechanisms specific to an individual subunit of different heterodimers is more useful. Thus, we describe the current understanding of and exploratory investigations on the α6-integrin subunit (CD49f, VLA6; encoded by the gene itga6) in normal and cancer cells. The roles of ITGA6 in cell adhesion, stemness, metastasis, angiogenesis, and drug resistance, and as a diagnosis biomarker, are discussed. The role of ITGA6 differs based on several features, such as cell background, cancer type, and post-transcriptional alterations. In addition, exosomal ITGA6 also implies metastatic organotropism. The importance of ITGA6 in the progression of a number of cancers, including hematological malignancies, suggests its potential usage as a novel prognostic or diagnostic marker and useful therapeutic target for better clinical outcomes.
... Epidermolysis bullosa (EB) is a rare, genetically inherited skin fragility disorder, causing mucocutaneous blistering, erosions, and ulceration as a result of even minor trauma [1]. Junctional EB (JEB) which is a type of EB is a skin disorder defined by dermal-epidermal junction fragility [2]. JEB is inherited via autosomal recessive mode. ...
... As a result of skin barrier breakdown, these patients develop septicemia, electrolyte disturbances, a loss of protein, and hypoalbuminemia, making septicemia the most common cause of neonatal death in these cases [3]. Intrauterine mechanical trauma may cause ACC, but the combination of ACC and JEB-PA suggests a common genetic basis for their pathogenesis [1,2]. We believe that if the disease is severe, intrauterine lesions can occur, which may cause ACC. ...
Epidermolysis bullosa (EB) is a rare and genetically inherited skin fragility disorder causing mucocutaneous blistering, erosion, and ulceration as a result of even minor trauma. Junctional EB (JEB), which is a type of EB, is inherited via an autosomal recessive pattern and characterized by blisters that appear in the lamina lucida of the basement membrane zone, which is the junction between the epidermis and dermis. The integrin genes (ITGA6, ITGB4) are responsible for the majority of JEB mutations. We present a case of lethal JEB and pyloric atresia with aplasia cutis congenita (ACC), with a homozygous pathogenic variant identified in the ITGA6 gene, c.1688dup. The diagnosis was made by whole exome sequencing (WES) postnatally after consecutive third pregnancy loss in the last trimester in a consanguineous couple. As these cases have a poor prognosis, genetic counseling, invasive prenatal testing, and preimplantation genetic diagnosis (PGD) have an evolving and indispensable role in the management of future pregnancies.
... The presence of IBD in these patients with ITGA6 mutations has not been disclosed, possibly because of the early lethality of complete human ITGA6 "knockout" within several weeks after birth (Figs. 2D, E). 9,10 In contrast, the 3-year-old patient reported here with a homozygous missense ITGA6 mutation lived long enough to display the IBD phenotype. ...
... Thus, mutations that functionally eliminate either the α6 or β4 subunit of this integrin complex or more subtle amino acid substitutions that interfere with the critical protein-protein interactions can result in fragility of the skin, manifesting with blistering and erosions as a result of minor trauma. 9,10 The α6β4 integrin is also present in the gastrointestinal epithelium, and it plays a critical role in the attachment of the intestinal epithelial cells to the underlying stroma (Fig. 2F). It has been previously reported that the ablation of α6 integrin in mouse intestinal epithelial cells led to hemidesmosome disruption and the development of inflammatory lesions with a high susceptibility for spontaneous development of colorectal adenocarcinomas. ...
... Cutaneous manifestations of JEB-PA include severe mucocutaneus blisters, extreme skin fragility, atrophic scarring, and milia (small white spots). JEB-PA is caused by mutations in the ITGA6 or ITGB4 genes coding for subunit alpha 6 (α6) or beta 4 (β4) of integrin [5,6]. Additional features shared by JEB-PA include aplasia cutis congenita (ACC) that means congenital localized absence of the skin affecting the extremities, head, nail dystrophy, scarring alopecia, enamel hypoplasia, contractures, and dilated cardiomyopathy [7][8][9]. ...
... as a template for each PCR reaction. Conditions and primers for generating PCR products spanning all exons of the coding regions and flanking intronic sequences of the genes have been previously described elsewhere [6,13]. After that, bidirectional Sanger sequencing analysis was performed using BigDye Terminator v3.1 Cycle Sequencing Kit on an ABI PRISM 3130 Genetic Analyzer (Thermo Fisher Scientific, Waltham, MA, USA). ...
Background
Epidermolysis bullosa with pyloric atresia (EB-PA), also known as Carmi syndrome, is an uncommon, autosomal recessive genodermatosis that typically affects the skin and gastrointestinal tract. EB-PA is caused by homozygous or compound heterozygous mutations in the integrin alpha 6 ( ITGA6 ) gene on chromosome 2q31.1 or in the integrin beta 4 ( ITGB4 ) gene on 17q25.1.
Case presentation
A male premature infant was born with aplasia cutis, atresia of the pylorus, and bilateral hydronephrosis. His clinical and imaging findings were compatible with EB-PA. A novel, small deletion of the last two bases in exon 6 and the first two nucleotides of intron 6 (c.565_566+2del) in ITGB4 gene was identified.
Conclusion
EB-PA-aplasia cutis congenita is known to be a non-treatable condition with a poor prognosis as the reported case. The novel mutation reported in this patient may lead to the lethal form of this disease. Identification of underlying genetic abnormality is critical to give genetic counseling.
... Vertebral anomalies were reported to range between 2% (Bailey et al. 1993) and 37% (Atwell and Klidkjian 1982) in these patients. Reports of duodenal atresia have also shown a low incidence of musculoskeletal anomalies (Pulkkinen et al. 1997). ...
The duodenum is the most common site of neonatal intestinal obstruction, accounting for 50% of all intestinal atresias. Duodenal obstruction (DO) is often complicated by prematurity and associated anomalies. Early prenatal ultrasonographic diagnosis of DO allows the mother karyotype analysis for trisomy 21 and other associated anomalies. Cardiac malformations are the major cause of morbidity and mortality in patients with congenital DO. For most causes of congenital DOs, duodenoduodenostomy via an open approach is the preferred surgical procedure. Vidal from France and Ernst from the Netherlands are credited with the first successful repairs in 1905 and 1914, respectively. Over the last decade, the application of minimally invasive surgical techniques (MIS) and the advent of smaller laparoscopic instruments have expanded the potential of laparoscopy for repair of congenital DO. The first reported laparoscopic repairs of duodenal atresia were by Bax in 2001 and Rothenberg in 2002. The last retrospective studies comparing the surgical outcome of laparoscopic repair versus open repair found that laparoscopy is a safe and effective technique, and the results including operative time, length of stay, time to full feeding, and complication rate were similar in both groups. The long-term survival rate of patients with DO is excellent and greater than 95% resulting from an early surgical intervention combined with advancement in neonatal intensive care, anesthesia, and nutritional support.
... The mouse null mutation of integrin α6 causes early postnatal death with aberration in the skin tissue (Georges-Labouesse et al., 1996). In human, homozygous mutation of the integrin α6 gene causes a skin disease with blisters (Pulkkinen et al., 1997). Integrin α6 contributes to radiotherapy resistance in breast cancer cells through activation of Akt and Erk signaling (Hu, Zhou, Zhao, & Wu, 2016). ...
Metastasis causes death in breast cancer patients. To inhibit breast cancer metastasis, we focused on integrin α6, a membrane protein that contributes to cell migration and metastasis. According to in silico analysis, we identified Asp‐358 as an integrin α6‐specific vertebrate‐conserved residue, and consequently as a potential therapeutic target. Because Asp‐358 is located on the surface of the β propeller domain that interacts with other molecules for integrin α6 function, we hypothesized that a peptide with the sequence around Asp‐358 competitively inhibits integrin α6 complex formation. We treated basal‐like breast cancer cells with the peptide and observed reductions in cell migration and metastasis. The result of the immunoprecipitation assay showed that the peptide inhibited integrin α6 complex formation. Our immunofluorescence for phosphorylated paxillin, a marker of integrin‐regulated focal adhesion, showed that the peptide reduced the number of focal adhesions. These results indicate that the peptide inhibits integrin α6 function. This study identified the functional residue of integrin α6 and designed the inhibitory peptide. For breast cancer patients, metastasis inhibition therapy may be developed in the future based on this study. This article is protected by copyright. All rights reserved.
... As indicated above, one such gene is PLEC which connects the intermediate keratin filaments to the β4 integrin within basal keratinocytes (Figure 1). The JEB-PA results from mutations in either ITGA6 or ITGB4, which encode α6 and β4 subunit polypeptides of α6β4 integrin, respectively (Vidal et al., 1995;Pulkkinen et al., 1997b;Pulkkinen et al., 1997a; M A N U S C R I P T ...
The heritable forms of epidermolysis bullosa (EB), a phenotypically heterogeneous group of skin fragility disorders, is currently associated with mutations in as many as 21 distinct genes. EB is primarily a disorder affecting the epithelial layers of skin and mucous membranes, without extracutaneous manifestations, and thus is nonsyndromic. However, recent demonstrations of skin blistering in multisystem disorders with single gene defects highlight the concept of syndromic EB. Here, we review the phenotypic and genotypic features of syndromic forms of EB to delineate the concept of syndromic versus nonsyndromic skin fragility disorders.
... Early in life patients with Kindler syndrome endure blistering of the skin and photosensitivity, which progresses to diffuse poikiloderma followed by cutaneous atrophy (16,17). The clinical presentation of this disease is similar to patients with junctional epidermolysis bullosa harboring mutations in ␣ 6 and  4 integrin genes (18,19). ...
... The kindlerin gene was recognized by linkage analysis as being mutated in a rare skin disease called Kindler syndrome. This disease is characterized by acral blistering, photosensitivity, and diffuse poikiloderma with cutaneous atrophy (1, 3) and shares some similarities in its clinical presentation with two subtypes of junctional epidermolysis bullosa that are caused by mutations in ␣ 6 or  4 integrin genes (18,19,52). Similar skin blistering phenotypes have been described in mice with disrupted ␣ 3 (53) (a major integrin partner for  1 integrin in the basolateral membrane of keratinocytes), ␣ 6 (54), and  4 (55) integrin genes as well as in mice genetically modified to specifically knock-out  1 integrin expression in skin (56,57). ...
Breast Cancer (BC) has associated risk factors and genetic factors like BRCA1, and BRCA2. Many benign and malignant disease processes are found concurrently with BC and believed to be additional risk factors like gall bladder stones (cholelithiasis), hypertension, diabetes mellitus, cerebrovascular lesions, arthritis, spine and spinal cord degenerative lesions, infertility, depression, sleep disturbances, obesity, autoimmune diseases (SLE), and thyroid diseases. There are some malignant disease associations like synchronous or metachronous ovarian, colonic and endometrial tumours with Breast cancer. Kindler Syndrome (KS) is a rare autosomal recessive genetic disorder manifesting as generalized dermatoses, described in 1954 by Theresa Kindler. KS is associated with acral skin blistering inducible by trauma, mucosal inflammation, photosensitivity, progressive pigmentation, telangiectasia, and skin atrophy (Poikiloderma). Repeated and progressive inflammation and subsequent fibrosis leads to ectropion, esophageal, anal, urethral, and vaginal stenosis and dryness. About 100 cases of Kindler syndrome have been reported in literature so far some from Arab World as well. Pathobiology of Kindler syndrome is not well understood. There are defects in KIND1 gene on chromosome 20. This gene expresses itself in basal keratinocytes, where it encodes a protein, called Kindlin 1. We report the second only case of Kindler's syndrome having breast cancer. These very very rare combinations have diagnostic issues, management restrictions, prognostic and follow up implications.
... Preclinical studies are necessary to identify the stage at which such a therapeutic approach would confer an optimal antimetastatic effect as well as potential side effects due to long-term treatment. It has been reported that defects in α6 integrin result in hemidesmosome deficiency and cause skin and mucous membrane disorders, such as pyloric atresia and epidermolysis bullosa, and, in most cases, early postnatal death (54,55). Whether a pharmacological strategy would result in such pathologies occurring during development is uncertain but will need to be tested. ...
Metastatic dissemination of cancer cells, which accounts for 90% of cancer mortality, is the ultimate hallmark of malignancy. Growing evidence suggests that blood platelets have a predominant role in tumor metastasis; however, the molecular mechanisms involved remain elusive. Here, we demonstrate that genetic deficiency of integrin α6β1 on platelets markedly decreases experimental and spontaneous lung metastasis. In vitro and in vivo assays reveal that human and mouse platelet α6β1 supports platelet adhesion to various types of cancer cells. Using a knockdown approach, we identified ADAM9 as the major counter receptor of α6β1 on both human and mouse tumor cells. Static and flow-based adhesion assays of platelets binding to DC-9, a recombinant protein covering the disintegrin-cysteine domain of ADAM9, demonstrated that this receptor directly binds to platelet α6β1. In vivo studies showed that the interplay between platelet α6β1 and tumor cell-expressed ADAM9 promotes efficient lung metastasis. The integrin α6β1-dependent platelet-tumor cell interaction induces platelet activation and favors the extravasation process of tumor cells. Finally, we demonstrate that a pharmacological approach targeting α6β1 efficiently impairs tumor metastasis through a platelet-dependent mechanism. Our study reveals a mechanism by which platelets promote tumor metastasis and suggests that integrin α6β1 represents a promising target for antimetastatic therapies.
... Preclinical studies are necessary to identify the stage at which such a therapeutic approach would confer an optimal antimetastatic effect as well as potential side effects due to long-term treatment. It has been reported that defects in α6 integrin result in hemidesmosome deficiency and cause skin and mucous membrane disorders, such as pyloric atresia and epidermolysis bullosa, and, in most cases, early postnatal death (54,55). Whether a pharmacological strategy would result in such pathologies occurring during development is uncertain but will need to be tested. ...
Metastatic dissemination of cancer cells, which accounts for 90% of cancer mortality, is the
ultimate hallmark of malignancy. Growing evidence suggests that blood platelets have a
predominant role in tumor metastasis; however, the molecular mechanisms involved remain
elusive. Here, we demonstrate that genetic deficiency of integrin α6β1 on platelets markedly
decreases experimental and spontaneous lung metastasis. In vitro and in vivo assays reveal that
human and mouse platelet α6β1 supports platelet adhesion to various types of cancer cells. Using a
knockdown approach, we identified ADAM9 as the major counter receptor of α6β1 on both human
and mouse tumor cells. Static and flow-based adhesion assays of platelets binding to DC-9, a
recombinant protein covering the disintegrin-cysteine domain of ADAM9, demonstrated that this
receptor directly binds to platelet α6β1. In vivo studies showed that the interplay between platelet
α6β1 and tumor cell–expressed ADAM9 promotes efficient lung metastasis. The integrin α6β1–
dependent platelet-tumor cell interaction induces platelet activation and favors the extravasation
process of tumor cells. Finally, we demonstrate that a pharmacological approach targeting α6β1
efficiently impairs tumor metastasis through a platelet-dependent mechanism. Our study reveals
a mechanism by which platelets promote tumor metastasis and suggests that integrin α6β1
represents a promising target for antimetastatic therapies.
