Yuka Toyomaki

Buschke–Ollendorff syndrome associated with hypertrophic scar formation: a possible role for LEMD3 mutation

mosome 6p22–24, which is not far away from PSORS1. Our study has some limitations. First, the identification of cases of schizophrenia and psoriasis relied on diagnostic codes in an administrative database. There remains a possibility of coding errors or misdiagnosis. Second, information about cigarette smoking, alcohol consumption and body mass index, which are associated with the risk of psoriasis, were not available in our dataset, leaving room for residual confounding. Third, as our data did not include complete information regarding medications taken, it is not possible for us to assess the confounding role of medications in the relationship between schizophrenia and psoriasis. In conclusion, our study suggests that there was a significant relationship between schizophrenia and psoriasis, particularly in women. Future molecular and genetic linkage studies are needed to elucidate the role of inflammatory processes in the pathomechanisms underlying the association between schizophrenia and psoriasis, as well as to explore the possibility of shared genetic aetiology.

Novel COL7A1 mutations in a Japanese family with transient bullous dermolysis of the newborn associated with pseudosyndactyly

Transient bullous dermolysis of the newborn (TBDN) is a neonatal blistering disease evident at birth or shortly thereafter. A key feature of TBDN is that the blistering decreases with increased age, and most lesions heal within several months to leave minimal scarring and pigmentation. Although the blistering can be widespread and occasionally affects the mucous membranes, TBDN rarely involves skeletal abnormalities such as pseudosyndactyly, so this subtype of epidermolysis bullosa (EB) is thought to be relatively benign. Retention of collagen VII within the epidermis is observed histologically, and dilated rough endoplasmic reticulum and inclusion bodies, known as stellate bodies, are visible by electron microscopy in basal ⁄suprabasal keratinocytes of the patient’s skin. We herein report novel COL7A1 gene mutations in a Japanese family with TBDN associated with pseudosyndactyly.

Diffuse and focal palmoplantar keratoderma can be caused by a keratin 6c mutation

The palmoplantar keratodermas (PPKs) are a large group of genodermatoses comprising nearly 60 genetically distinct diseases. They are characterized by hyperkeratosis on the palms and soles with or without extrapalmoplantar hyperkeratotic lesions. Focal PPK is one of the hallmarks of pachyonychia congenita, a rare autosomal dominant disorder resulting from mutations in the keratin genes KRT6A, KRT6B, KRT16 or KRT17. Recently, in‐frame deletion mutations of KRT6C have been identified in three families with focal PPK with slight or no nail changes. We report here a novel KRT6C mutation identified in a Japanese family with PPK with phenotypic heterogeneity, presenting with not only focal but also diffuse hyperkeratosis. The proband had diffuse hyperkeratosis on the soles and small focal hyperkeratoses on the palms, while the two other affected individuals showed focal hyperkeratoses on the soles. All three patients were heterozygotes for c.1414G>A in KRT6C, predicted to result in p.Glu472Lys. These findings strongly suggest that screening of patients with nonepidermolytic diffuse PPK, in whom the pathogenic mutations are yet to be determined, might identify mutations in KRT6C.

Two Japanese familial cases of punctate palmoplantar keratoderma caused by a novel AAGAB mutation, c.191_194delCAAA

o Japanese familial cases of punctate lmoplantar keratoderma caused by a vel AAGAB mutation, c.191_194delCAAA the pressure-bearing areas of the plantar skin [1,2]. Recently, two consecutive studies identified that PPPK1 was caused by mutations in the AAGAB gene, encoding alphaand gamma-adaptin binding protein p34 (p34) [1,2]. Subsequently, several AAGAB mutations were reported in PPPK1 families from Europe, the Middle East, and Asia [1–8]. Here, we describe two Japanese PPPK1 pedigrees harboring the same, novel AAGAB mutation. This work was conducted in accordance with the Declaration of Helsinki ywords: lmoplantar keratoderma;

Calcineurin/NFAT-dependent regulation of 230-kDa bullous pemphigoid antigen (BPAG1) gene expression in normal human epidermal keratinocytes

BACKGROUND AND OBJECTIVE Cyclosporin A (CsA) is utilized widely for treatment of inflammatory skin diseases, such as psoriasis vulgaris. The therapeutic effects of CsA are thought to be mediated by its immunosuppressive action on infiltrating lymphocytes in the lesional skin. CsA also inhibits epidermal keratinocyte proliferation, suggesting a direct biological action on keratinocytes. Here we tested the hypothesis that CsA can modulate the expression of the nuclear factor of activated T-cell (NFAT) in epidermal keratinocytes. We also investigated whether the keratinocyte-specific gene expression is modified by CsA through NFAT activity in association with differentiation induction. METHODS RT-PCR was performed using total RNAs extracted from cultured normal human epidermal keratinocytes (NHEK), normal human dermal fibroblasts (NHDF), and normal human epidermal melanocytes (NHEM) for detecting NFAT isomolecules. Transient transfections of NHEK with a 230-kDa bullous pemphigoid antigen (BPAG1) promoter/luciferase reporter gene and the luciferase assay were conducted for examining the effect of CsA on the promoter activity of the BPAG1 gene. Electrophoretic gel mobility shift assays (EMSA) with probes containing NFAT consensus sequences for analyzing the binding activities of the nuclear proteins extracted from NHEK. RESULTS RT-PCR revealed expression of all of the five isoforms of NFAT in the cell lines examined. The mRNA expression levels of NFAT1, NFAT2, BPAG1, and involucrin were downregulated by CsA treatment in NHEK. The luciferase assay indicated suppression of the promoter activity by CsA. EMSA with NFAT consensus probes identified in the BPAG1 promoter region demonstrated specific binding activity in the nuclear proteins of epidermal keratinocytes. CONCLUSION As reported previously, our results indicate that epidermal keratinocytes possess calcineurin/NFAT system, which is suppressed by CsA. In addition, the data suggest that CsA can downregulate the BPAG1 gene expression perhaps via the NFAT consensus cis-elements in the BPAG1 promoter region. Such transcriptional regulatory system might be involved in the regulation of keratinocyte differentiation and proliferation.

A novel H1 domain mutation in the keratin 2 gene in a Japanese family with ichthyosis bullosa of Siemens.

Ichthyosis bullosa of Siemens (IBS) is a rare autosomal dominant skin disorder characterized by blister formation in the upper suprabasal layers of the epidermis. Clinical features of the disease, which include blistering after mechanical trauma, lichenified hyperkeratosis over the flexural areas of the limbs, and superficial peeling of the skin, are similar to those of epidermolytic hyperkeratosis/bullous congenital ichthyosiform erythroderma (EHK/BCIE). This clinical resemblance makes diagnosis difficult. Recent molecular studies have identified mutations in the keratin 2 (K2) gene (KRT2; this new designation is used throughout this report according to the current nomenclature for mammalian keratins) in patients with IBS, in contrast to the keratin 1 or 10 mutations that have been detected in patients with EHK/BCIE, enabling us to differentiate between IBS and EHK/BCIE. Thus far, 29 missense mutations that result in amino acid substitutions in K2 have been identified in patients with IBS; all such mutations reside in the helix initiation or termination motifs of K2. Here, we describe a novel mutation in the H1 region of K2 in a Japanese family with IBS.

Rubinstein-Taybi syndrome with multiple pilomatricomas: The first case diagnosed by CREBBP mutation analysis

Rubinstein-Taybi syndrome (RTS, OMIM #180849, #613684) is a rare genetic disorder characterized by mental retardation and multiple congenital anomalies. Although approximately 60% of cases are reportedly associated with mutations in the CREBBP gene [1] or the EP300 gene [2], the etiology of RTS is heterogeneous and remains to be elucidated. The cAMP-response element-binding protein-binding protein (CREBBP) encoded by CREBBP has a histone acetyl/lysine-transferase (HAT or KAT) activity and function as a transcription co-activator, with more than 400 described interaction partners, regulating the expression of many genes during development and postnatal life [3]. RTS is associated with an increased risk for development of tumors such as lymphoma, leukemia and neural tumors [1]. RTS is also known to be accompanied with multiple pilomatricomas, however, only six cases have been reported to date [4–6]. Furthermore, characteristics of CREBBP mutations in these cases are unknown. A recent case report described a CREBBP mutation (c.6127C > T, p. Q2043X) in an RTS patient who developed a solitary pilomatricoma on the scalp [7]. However, the association between the development of pilomatricoma and CREBBP mutations needs to be discussed further. Pilomatricoma is a non-hereditary benign tumor which is considered to be derived from the hair matrix. Stabilizing mutations in b-catenin, which is encoded by CTNNB1, are known to be involved in the development of pilomatricomas [8]. Multiple pilomatricomas have been reported to be associated with other genetic disorders, Turner syndrome, Gardner syndrome, Sotos syndrome, and Kabuki syndrome; the most frequent association is with myotonic dystrophy. Herein, we present the first report of a CREBBP mutation in an RTS patient with multiple pilomatricomas. The proband is a 12-year-old girl, referred to our department for the evaluation and treatment of multiple congenital hard tumors. Consanguineous marriage was denied by the parents. She had two brothers and her family history was unremarkable. On physical examination, she had a short stature (139 cm) and obesity (45 kg). Clinical features included characteristic facial dysmorphia (higharched eyebrows and prominent nose with nasal septum extending below the alae nasi), broad thumbs and halluces (Fig. 1A), intellectual disability, and suspected optic nerve atrophy. The patient had seven stony-hard tumors on her neck (Fig. 1B), arms, and trunk. All tumors were surgically excised under general anesthesia. Histology revealed that all the resected tumors had basophilic cells and shadow cells with partial ossification (Fig. 1C); they were diagnosed as pilomatricomas. Based on these clinical features, the patient was diagnosed as RTS.

Novel p.M1T and recurrent p.G301S mutations in cathepsin C in a Japanese patient with Papillon-Lefèvre syndrome : Implications for understanding the genotype/phenotype relationship

[1] Benjamin CL, Ananthaswamy HN. P53 and the pathogenesis of skin cancer. Toxicol Appl Pharmacol 2007;224:242–8. [2] Perez MI, Robins P, Biria S, Roco J, Siegel E, Pellicer A. P53 oncoprotein expression and gene mutations in some keratoacanthomas. Arch Dermatol 1997;133: 189–93. [3] Borkowski A, Bennett WP, Jones RT, Borkowski P, Harris CC, Ferreira LR, et al. Quantitative image analysis of p53 protein accumulation in keratoacanthomas. Am J Dermatopathol 1995;17:335–8. [4] Putti TC, Teh M, Lee YS. Biological behavior of keratoacanthoma and squamous cell carcinoma: telomerase activity and COX-2 as potential markers. Mod Pathol 2004;17:468–75. [5] Burnworth B, Arendt S, Muffler S, Steinkraus V, Bröcker EB, Birek C, et al. The multi-step process of human skin carcinogenesis: a role for p53, cyclin D1, hTERT, p16, and TSP-1. Eur J Cell Biol 2007;86:763–80. [6] Ribeiro D, Narikawa S, Marques ME. Expression of apoptotic and cell proliferation regulatory proteins in keratoacanthomas and squamous cell carcinomas of the skin. Pathol Res Pract 2008;204:97–104. [7] Kerschmann RL, McCalmont TH, LeBoit PE. p53 oncoprotein expression and proliferation index in keratoacanthoma and squamous cell carcinoma. Arch Dermatol 1994;130:181–6. [8] Kubo Y, Urano Y, Yoshimoto K, Iwahana H, Fukuhara K, Arase S, et al. p53 gene mutations in human skin cancers and precancerous lesions: comparison with immunohistochemical analysis. J Invest Dermatol 1994;102:440–4.

Dominant dystrophic epidermolysis bullosa caused by a novel G2037R mutation and by a known G2028R mutation in the type VII collagen gene (COL7A1)

An autosomal dystrophic epidermolysis bullosa (DDEB) is a hereditary mechanobullous disease characterized by blistering of the skin and the mucous membrane. DDEB is caused by a heterozygous mutation in the COL7A1 gene encoding type VII collagen, the major component of anchoring fibrils, and phenotypically classified into several types. We experienced two boys with DDEB and examined the mutation analyses of the COL7A1 genes of the two patients and their fathers to clarify the relationship between the genotypes and phenotypes, that is, the mutation sites of COL7A1 gene and the clinical types of DDEB. The case 1 and 2 patients and their fathers revealed a heterozygous nucleotide G to A transition at position 6109 and 6082 in 73 exon of COL7A1, which resulted in a glycine to arginine substitution (G2037R and G2028R), respectively. G2037R found in the case 1 patient was a novel mutation. There was no clear relationship recognized between the two mutation sites in the COL7A1 gene and the clinical variations.

Multiple Milia as an Isolated Skin Manifestation of Dominant Dystrophic Epidermolysis Bullosa: Evidence of Phenotypic Variability

We report a Japanese pedigree with dominant dystrophic epidermolysis bullosa (DDEB) harboring the p.G2251E mutation of COL7A1. The proband of this pedigree presented with multiple milia as an isolated skin manifestation without a history of blistering and subsequently developed generalized intractable blisters, suggesting that multiple milia could be a primary manifestation of DDEB. Her mother exhibited nail dystrophy and pruritic nodules and her elder sister was unaffected, despite having the same COL7A1 mutation. Inter‐ and intrafamilial clinical variability are often observed in DDEB, so we should be aware of this factor to provide appropriate genetic counselling.