Keratinocytes of the Upper Epidermis and Isthmus of Hair Follicles Express Hemoglobin mRNA and Protein.

The epidermis, the keratinized stratified squamous epithelium surrounding the body surface, offers a valuable framework to investigate how terrestrial animals overcome environmental stresses. However, the mechanisms underlying epidermal barrier function remain nebulous. In this study, we examined genes highly expressed in the human and mouse upper epidermis, the outer frontier that induces various barrier-related genes. Transcriptome analysis revealed that the messenger RNA level of hemoglobin α (HBA), an oxygen carrier in erythroid cells, was enriched in the upper epidermis compared with that in the whole epidermis. Immunostaining analysis confirmed HBA protein expression in human and mouse keratinocytes (KCs) of the stratum spinosum and stratum granulosum. HBA was also expressed in hair follicle KCs in the isthmus region; its expression levels were more prominent than those in interfollicular KCs. HBA expression was not observed in noncutaneous keratinized stratified squamous epithelia of mice, for example, the vagina, esophagus, and forestomach. HBA expression was upregulated in human epidermal KC cultures after UV irradiation, a major cause of skin-specific oxidative stress. Furthermore, HBA knockdown increased UV-induced production of ROS in primary KCs. Our findings suggest that epidermal HBA expression is induced by oxidative stress and acts as an antioxidant, contributing to skin barrier function.

Solitary fibrous tumor of the breast: A case report.

INTRODUCTION: Solitary fibrous tumors (SFTs) are uncommon mesenchymal neoplasms that comprise <2 % of all soft tissue tumors. They are a diagnostically challenging group of neoplasms that can occur essentially anywhere. Molecular or genetic testing of soft tissue tumors will increasingly add to the foundation of distinctive histologic features, as accurate diagnosis is critical for appropriate treatment. CASE PRESENTATION: A 28-year-old woman was referred to our hospital for a left breast mass. Ultrasonography showed an oval hypoechoic mass with partially obscured boundaries. Surgical specimens revealed spindle tumor cells surrounding the mammary ducts and were immunoreactive for both CD34 and STAT6, suggesting SFTs. However, the infiltration of spindle tumor cells into the surrounding fat, and the storiform-like pattern made us consider dermatofibrosarcoma protuberans (DFSP) as a differential diagnosis. Lack of amplification of the COL1A1-PDGFB fusion gene, a characteristic feature of DFSP, led to our definitive diagnosis of breast SFT. DISCUSSION: The presence of STAT6 in tumor cell nuclei is a highly sensitive immunohistochemical marker for SFT. In our case, morphological features evoked the differential diagnosis of DFSP and we investigated the COL1A1-PDGFB fusion gene. The diagnostic process of reliably performing careful morphological examination and immunohistochemical marker test, and then obtain conviction by molecular cytogenetic technique is more and more important for soft tissue tumors. CONCLUSIONS: We report a quite uncommon case of breast SFT and excluded DFSP as a differential diagnosis. If it is difficult to distinguish between these diseases, molecular cytogenetic analysis would be required for accurate diagnosis.

Two sporadic cases of childhood-onset Hailey-Hailey disease with superimposed mosaicism.

A prenatal second-hit genetic change that occurs on the wild-type allele in an embryo with a congenital pathogenic variant allele results in mosaicism of monoallelic and biallelic defect of the gene, which is called superimposed mosaicism. Superimposed mosaicism of Hailey-Hailey disease (HHD) has been demonstrated in one familial case. Here, we report two unrelated HHD cases with superimposed mosaicism: a congenital monoallelic pathogenic variant of ATP2C1, followed by a postzygotic copy-neutral loss of heterozygosity. Uniquely, neither patient had a family history of HHD at the time of presentation. In the first case, the congenital pathogenic variant had occurred de novo. In the second case, the father had the pathogenic variant but had not yet developed skin symptoms. Our cases showed that superimposed mosaicism in HHD can lack a family history and that genetic analysis is crucial to classify the type of mosaicism and evaluate the risk of familial occurrence.

Zonula occludens-1 distribution and barrier functions are affected by epithelial proliferation and turnover rates.

Zonula occludens-1 (ZO-1) is a scaffolding protein of tight junctions, which seal adjacent epithelial cells, that is also expressed in adherens junctions. The distribution pattern of ZO-1 differs among stratified squamous epithelia, including that between skin and oral buccal mucosa. However, the causes for this difference, and the mechanisms underlying ZO-1 spatial regulation, have yet to be elucidated. In this study, we showed that epithelial turnover and proliferation are associated with ZO-1 distribution in squamous epithelia. We tried to verify the regulation of ZO-1 by comparing normal skin and psoriasis, known as inflammatory skin disease with rapid turnover. We as well compared buccal mucosa and oral lichen planus, known as an inflammatory oral disease with a longer turnover interval. The imiquimod (IMQ) mouse model, often used as a psoriasis model, can promote cell proliferation. On the contrary, we peritoneally injected mice mitomycin C, which reduces cell proliferation. We examined whether IMQ and mitomycin C cause changes in the distribution and appearance of ZO-1. Human samples and mouse pharmacological models revealed that slower epithelial turnover/proliferation led to the confinement of ZO-1 to the uppermost part of squamous epithelia. In contrast, ZO-1 was widely distributed under conditions of faster cell turnover/proliferation. Cell culture experiments and mathematical modelling corroborated these ZO-1 distribution patterns. These findings demonstrate that ZO-1 distribution is affected by epithelial cell dynamics.

Neurofibromatosis type 2 with mild Pierre-Robin sequence showing a heterozygous chromosome 22q12 microdeletion encompassing NF2 and MN1.

Pierre-Robin sequence (PRS) is a rare, congenital defect presenting with micrognathia, glossoptosis, and airway obstruction with variable inclusion of a cleft palate. Overlapping PRS with neurofibromatosis type 2 (NF2) is a syndrome caused by a chromosome 22q12 microdeletion including NF2. We describe a patient with severe early-onset NF2 overlapping with PRS that showed micrognathia, glossoptosis, and a mild form of cleft palate. We detected a de novo chromosome 22q12 microdeletion including MN1 and NF2 in the patient. Previous cases of overlapping PRS and NF2 caused by the chromosome 22q12 microdeletions showed severe NF2 phenotypes with variable severity of cleft palate and microdeletions of varying sizes. Genotype-phenotype correlations and comparison of the size and breakpoint of microdeletions suggest that some modifier genes distal to MN1 and NF2 might be linked to the cleft palate severity.

Acral peeling in Nagashima type palmo-plantar keratosis patients reveals the role of serine protease inhibitor B 7 in keratinocyte adhesion.

Acral peeling skin syndrome (APSS) is a heterogenous group of genodermatoses, manifested by peeling of palmo-plantar skin and occasionally associated with erythema and epidermal thickening. A subset of APSS is caused by mutations in protease inhibitor encoding genes, resulting in unopposed protease activity and desmosomal degradation and/or mis-localization, leading to enhanced epidermal desquamation. We investigated two Arab-Muslim siblings with mild keratoderma and prominent APSS since infancy. Genetic analysis disclosed a homozygous mutation in SERPINB7, c.796C > T, which is the founder mutation in Nagashima type palmo-plantar keratosis (NPPK). Although not previously formally reported, APSS was found in other patients with NPPK. We hypothesized that loss of SERPINB7 function might contribute to the peeling phenotype through impairment of keratinocyte adhesion, similar to other protease inhibitor mutations that cause APSS. Mis-localization of desmosomal components was observed in a patient plantar biopsy compared with a biopsy from an age- and gender-matched healthy control. Silencing of SERPINB7 in normal human epidermal keratinocytes led to increased cell sheet fragmentation upon mechanical stress. Immunostaining showed reduced expression of desmoglein 1 and desmocollin 1. This study shows that in addition to stratum corneum perturbation, loss of SERPINB7 disrupts desmosomal components, which could lead to desquamation, manifested by skin peeling.

Differential Pathomechanisms of Desmoglein 1 Transmembrane Domain Mutations in Skin Disease.

Dominant and recessive mutations in the desmosomal cadherin, desmoglein (DSG) 1, cause the skin diseases palmoplantar keratoderma (PPK) and severe dermatitis, multiple allergies, and metabolic wasting (SAM) syndrome, respectively. In this study, we compare two dominant missense mutations in the DSG1 transmembrane domain (TMD), G557R and G562R, causing PPK (DSG1PPK-TMD) and SAM syndrome (DSG1SAM-TMD), respectively, to determine the differing pathomechanisms of these mutants. Expressing the DSG1TMD mutants in a DSG-null background, we use cellular and biochemical assays to reveal the differences in the mechanistic behavior of each mutant. Super-resolution microscopy and functional assays showed a failure by both mutants to assemble desmosomes due to reduced membrane trafficking and lipid raft targeting. DSG1SAM-TMD maintained normal expression levels and turnover relative to wildtype DSG1, but DSG1PPK-TMD lacked stability, leading to increased turnover through lysosomal and proteasomal pathways and reduced expression levels. These results differentiate the underlying pathomechanisms of these disorders, suggesting that DSG1SAM-TMD acts dominant negatively, whereas DSG1PPK-TMD is a loss-of-function mutation causing the milder PPK disease phenotype. These mutants portray the importance of the DSG TMD in desmosome function and suggest that a greater understanding of the desmosomal cadherin TMDs will further our understanding of the role that desmosomes play in epidermal pathophysiology.

Japanese guidelines for the management of palmoplantar keratoderma.

Palmoplantar keratoderma (PPK) is a collective term for keratinizing disorders in which the main clinical symptom is hyperkeratosis on the palms and soles. To establish the first Japanese guidelines approved by the Japanese Dermatological Association for the management of PPKs, the Committee for the Management of PPKs was founded as part of the Study Group for Rare Intractable Diseases. These guidelines aim to provide current information for the management of PPKs in Japan. Based on evidence, they summarize the clinical manifestations, pathophysiologies, diagnostic criteria, disease severity determination criteria, treatment, and treatment recommendations. Because of the rarity of PPKs, there are only few clinical studies with a high degree of evidence. Therefore, several parts of these guidelines were established based on the opinions of the committee. To further optimize the guidelines, periodic revision in line with new evidence is necessary.

Premature aging syndrome showing random chromosome number instabilities with CDC20 mutation.

Damage to the genome can accelerate aging. The percentage of aneuploid cells, that is, cells with an abnormal number of chromosomes, increases during aging; however, it is not clear whether increased aneuploidy accelerates aging. Here, we report an individual showing premature aging phenotypes of various organs including early hair loss, atrophic skin, and loss of hematopoietic stem cells; instability of chromosome numbers known as mosaic variegated aneuploidy (MVA); and spindle assembly checkpoint (SAC) failure. Exome sequencing identified a de novo heterozygous germline missense mutation of c.856C>A (p.R286S) in the mitotic activator CDC20. The mutant CDC20 showed lower binding affinity to BUBR1 during the formation of the mitotic checkpoint complex (MCC), but not during the interaction between MCC and the anaphase-promoting complex/cyclosome (APC/C)-CDC20 complex. While heterozygous knockout of CDC20 did not induce SAC failure, knock-in of the mutant CDC20 induced SAC failure and random aneuploidy in cultured cells, indicating that the particular missense mutation is pathogenic probably via the resultant imbalance between MCC and APC/C-CDC20 complex. We postulate that accelerated chromosome number instability induces premature aging in humans, which may be associated with early loss of stem cells. These findings could form the basis of a novel disease model of the aging of the body and organs.