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Featured researches published by Eijiro Akasaka.


The FASEB Journal | 2008

Epistatic connections between microphthalmia-associated transcription factor and endothelin signaling in Waardenburg syndrome and other pigmentary disorders

Kayo Sato-Jin; Emi K. Nishimura; Eijiro Akasaka; Wade E. Huber; Hajime Nakano; Arlo J. Miller; Jinyan Du; Min Wu; Katsumi Hanada; Daisuke Sawamura; David E. Fisher; Genji Imokawa

Waardenburg syndrome (WS) is an inherited sensorineural deafness condition in humans caused by melanocyte deficiencies in the inner ear and forelock. Mutation of microphthalmia‐associated transcription factor (MITF) is known to produce WS type IIA whereas mutations of either endothelin (EDN) or its receptor endothelin receptor B (EDNRB) produce WS type IV. However, a link between MITF haploinsuf‐ficiency and EDN signaling has not yet been established. Here we demonstrate mechanistic connections between EDN and MITF and their functional importance in melanocytes. Addition of EDN to cultured human melanocytes stimulated the phosphorylation of MITF in an EDNRB‐dependent manner, which was completely abolished by mitogen‐activated protein kinase kinase inhibition. The expression of melanocyte‐specific MITF mRNA transcripts was markedly augmented after incubation with EDN1 and was followed by increased expression of MITF protein. Up‐regulated expression of MITF was found to be mediated via both the mitogen‐activated protein kinase‐p90 ribo‐somal S6 kinase‐cAMP response element‐binding protein (CREB) and cAMP‐protein kinase A‐CREB pathways. In addition, EDNRB expression itself was seen to be dependent on MITF. The functional importance of these connections is illustrated by the ability of EDN to stimulate expression of melanocytic pigmentation and proliferation markers in an MITF‐dependent fashion. Collectively these data provide mechanistic and epi‐static links between MITF and EDN/EDNRB, critical melanocytic survival factors and WS genes. Sato‐Jin, K., Nishimura, E. K., Akasaka, E., Huber, W., Nakano, H., Miller, A., Du, J., Wu, M., Hanada, K., Sawamura, D., Fisher, D. E., Imokawa, G. Epistatic connections between microphthalmia‐associated transcription factor and endothelin signaling in Waardenburg syndrome and other pigmentary disorders. FASEB J. 22, 1155–1168 (2008)


Journal of Dermatological Science | 2012

Characterization of retinoic acid-inducible gene-I (RIG-I) expression corresponding to viral infection and UVB in human keratinocytes

Kazuyuki Kimura; Yasushi Matsuzaki; Yohei Nishikawa; Hideo Kitamura; Eijiro Akasaka; Daiki Rokunohe; Hajime Nakano; Tadaatsu Imaizumi; Kei Satoh; Daisuke Sawamura

BACKGROUND Retinoic acid-inducible gene-I (RIG-I) is a cytoplasmic protein that recognizes viral double-stranded RNA to induce the type I interferon (IFN) response. In human keratinocytes, RIG-I is induced by IFN-γ and tumor necrosis factor-α stimulation, and is abundantly expressed in psoriatic keratinocytes of the spinous and basal layers. OBJECTIVE This study investigated the effects of extraneous stimuli including viral infection and UVB exposure on RIG-I expression in human keratinocytes. METHODS Human skin keratinocytes (HaCaT cells) were stimulated by polyinosinic-polycytidylic acid (poly(I:C)), which mimics viral infection, and UVB exposure. We assessed the expression of RIG-I and IFN-regulatory factor (IRF)-1 in HaCaT cells by RT-PCR and Western blot analysis. Moreover, we investigated the effect of IRF-1 binding site of RIG-I gene promoter on the regulation of RIG-I expression by luciferase promoter assay and electrophoretic mobility shift assay. RESULTS Poly(I:C) induced RIG-I expression, while UVB inhibited basal RIG-I expression and the poly(I:C)-induced RIG-I overexpression in HaCaT cells. IRF-1, which binds to a regulatory element located on the RIG-I gene promoter, was required for both inductions of RIG-I expression. IRF-1 expression was enhanced three hours after the poly(I:C) stimulation, consistent with the RIG-I response to poly(I:C), and thereafter was suppressed. Moreover, UVB exposure promptly decreased IRF-1 expression, resulting in decreased IRF-1 protein binding to the RIG-I promoter, and consequently, decreased RIG-I expression. CONCLUSION Thus, suppression of RIG-I and IRF-1 expression caused by UVB exposure may partly explain the inhibition of skin-based immune responses, leading to viral infection and recrudescence.


British Journal of Dermatology | 2011

Vörner type palmoplantar keratoderma: novel KRT9 mutation associated with knuckle pad-like lesions and recurrent mutation causing digital mutilation

Noriko Umegaki; H. Nakano; Katuto Tamai; Yoshihiko Mitsuhashi; Eijiro Akasaka; Daisuke Sawamura; Ichiro Katayama

Epidermolytic palmoplantar keratoderma, Vörner type (EPPK, OMIM 144200) is an autosomal dominantly inherited skin disease caused by mutations in the keratin 9 gene (KRT9) and rarely in the keratin 1 gene. This condition is characterized by diffuse yellow thickening of the skin of the palms and soles, sharply offset by erythematous margins. Histopathologically, EPPK presents the characteristic features of epidermolytic hyperkeratosis. This report concerns two Japanese EPPK families with associated characteristic cutaneous manifestations: knuckle pad-like lesions associated with a novel nonsense KRT9 mutation and digital mutilation caused by a recurrent KRT9 mutation. The proband of family 1 was a 12-year-old Japanese girl presenting with hyperkeratosis of palms and soles since soon after birth (Fig. 1a). Hypertrophic plaques with erythema were noted on the dorsal aspects of the distal phalanges of the hands (Fig. 1a, lower panel). Similar lesions, but to a lesser extent, were seen on the toes (not shown). No other family members were affected. Histopathology showed epidermolytic hyperkeratosis with large irregular keratohyaline granules and vacuolization of keratinocytes in the upper spinous and granular layers (not shown). The proband of family 2 was a 58-year-old Japanese woman presenting with hyperkeratosis of palms and soles that developed soon after birth. Her father and elder sister had similar hyperkeratotic skin changes. In the second decade of her life, t‘he proband first noted that the fifth toes felt mildly constricted. Since then, the constriction gradually progressed with accompanying numbness of the fifth toes. When she was 50 years old, the constricted fifth toes became detached spontaneously with no traumatic aetiology (Fig. 1b, arrows). Slight constriction of the finger joints of the proband was observed, especially of the middle interphalangeal joints (Fig. 1b, arrowheads). The other affected individuals did not show any constrictive changes in their fingers or toes nor any knuckle pad-like lesions. Histopathology indicated epidermolytic hyperkeratosis with vacuolization of the granular layer (not shown). Genomic DNA samples extracted from the probands and their family members were subjected to mutation analyses. In the probands, all the KRT9 exons and their flanking exon ⁄ intron junctions were amplified by polymerase chain reaction (PCR) and the PCR products were directly sequenced. Mutational analysis revealed a C-to-T transition at nucleotide position 1282 (c.1282C>T) in exon 6 of KRT9 in the proband of family 1 (Fig. 2a), but not in the healthy parents, suggestBJD British Journal of Dermatology


British Journal of Dermatology | 2012

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

Ayumi Korekawa; H. Nakano; Yuka Toyomaki; Noriko Takiyoshi; Daiki Rokunohe; Eijiro Akasaka; Koji Nakajima; Daisuke Sawamura

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.


British Journal of Dermatology | 2011

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

Eijiro Akasaka; H. Nakano; A. Nakano; Yuka Toyomaki; Noriko Takiyoshi; Daiki Rokunohe; Yohei Nishikawa; Ayumi Korekawa; Yasushi Matsuzaki; Yoshihiko Mitsuhashi; Daisuke Sawamura

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.


Journal of Dermatological Science | 2015

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

Eijiro Akasaka; Yuko Okawa; Hajime Nakano; Noriko Takiyoshi; Daiki Rokunohe; Yuka Toyomaki; Daisuke Sawamura; Hirohiko Sueki

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;


Journal of Dermatology | 2010

Linear immunoglobulin A bullous dermatosis possibly induced by mefenamic acid

Kayo Jin; Hajime Nakano; Eijiro Akasaka; Daiki Rokunohe; Satoko Minagawa; Norito Ishii; Takashi Hashimoto; Daisuke Sawamura

Dear Editor, Linear immunoglobulin A bullous dermatosis (LABD) is a relatively rare autoimmune blistering disease characterized clinically by the presence of small tense blisters and immunologically by the presence of immunoglobulin (Ig)A at the dermal–epidermal junction. Idiopathic, systemic disease-related and drugrelated types of this disorder have been described so far. We report the first case of LABD possibly associated with mefenamic acid, which is well known to induce commonly fixed drug eruptions. A 69-year-old Japanese woman presented with multiple blisters and erosions on her trunk, hip and thighs. She first noticed the skin eruption after taking mefenamic acid for 7 days for treatment of a common cold and the skin lesions were only a few blisters at the beginning. She visited a dermatology practitioner and a diagnosis of fixed drug eruption by mefenamic acids was made. Thus, she was given an oral antihistaminic drug and topical corticosteroid ointment. However, the eruption exacerbated and she was then referred to our clinic. Physical examination revealed some tense bullae and edematous erythema with vesiculobullae and erosions arranged annularly on her trunk, hip, thighs and upper extremities (Fig 1a,b). Mucosal lesions were not found in mucous membranes and there were no scars and milia. History taking revealed that the patient had experienced a similar eruption after taking mefenamic acids approximately 7 years before visiting us. Histological examination showed a subepidermal blister with a dense inflammatory infiltrate of lymphocytes, neutrophils and eosinophils in the edematous superficial dermis. Acantholysis and papillary abscess were not seen. All the laboratory data obtained were within normal limits. Direct immunofluorescent study revealed linear deposits of IgA and IgG at the basement membrane


British Journal of Dermatology | 2009

Novel and recurrent nonsense mutation of the SLC39A4 gene in Japanese patients with acrodermatitis enteropathica

Hajime Nakano; Y. Nakamura; Tatsuyoshi Kawamura; Naotaka Shibagaki; H. Matsue; Takayuki Aizu; Daiki Rokunohe; Eijiro Akasaka; Kazuyuki Kimura; A. Nishizawa; Noriko Umegaki; Yoshihiko Mitsuhashi; S. Shimada; Daisuke Sawamura

Acrodermatitis enteropathica (AE, OMIM 201100) is a rare autosomal recessive disease characterized by hypozincaemia derived from the inability to absorb intestinal zinc. The clinical manifestations of AE include growth retardation, diarrhoea, alopecia, repeated infections due to immune dysfunction, and characteristic skin lesions on acral and periorificial areas. The hypozincaemia in AE is believed to be caused by a defect in a zinc transporting protein. Recently, the gene encoding this zinc transporting protein was identified on chromosomal region 8q24.3, and subsequently SLC39A4 located on the chromosome was identified as the AE gene. SLC39A4 encodes the ZIP4 zinc transporter, which transports zinc into the cytoplasm, mainly in the intestine. Here, we report two Japanese families with AE, in which a novel nonsense mutation in the SCL39A4 gene was identified.


Journal of Dermatological Science | 2016

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

Daiki Rokunohe; Hajime Nakano; Eijiro Akasaka; Yuka Toyomaki; Daisuke Sawamura

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.


Journal of Dermatological Science | 2009

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

Toyoko Ochiai; Hajime Nakano; Daiki Rokunohe; Eijiro Akasaka; Yuka Toyomaki; Yoshihiko Mitsuhashi; Daisuke Sawamura

[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.

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