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ABSTRACT: Reticulate acropigmentation of Kitamura (RAK) is a rare genetic disorder of cutaneous pigmentation with an autosomal dominant pattern of inheritance and a high penetration rate. The characteristic skin lesions are reticulate, slightly depressed pigmented macules mainly affecting the dorsa of the hands and feet, which first appear before puberty and subsequently expand to the proximal limb and the trunk. To identify mutations that cause RAK, we performed exome sequencing of 4 family members in a pedigree with RAK. 53 SNV/Indels were considered as candidate mutations after some condition narrowing. We confirmed the mutation status in each candidate gene of 4 other members in the same pedigree to find the gene that matched the mutation status and phenotype of each member. A mutation in ADAM10 encoding a zinc metalloprotease, a disintegrin and metalloprotease domain-containing protein 10 (ADAM10) was identified in the RAK family. ADAM10 is known to be involved in the ectodomain shedding of various substrates in the skin. Sanger sequencing of 4 additional unrelated RAK patients revealed 4 additional ADAM10 mutations. We identified a total of 3 truncating mutations, a splice site mutation and a missense mutation in ADAM10. We searched for mutations in the KRT5 gene, a causative gene for the similar pigmentation disorder Dowling-Degos disease, in all the patients and found no KRT5 mutation. These results reveal that mutations in ADAM10 are a cause of RAK and that RAK is an independent clinical entity distinct from Dowling-Degos disease.
Human Molecular Genetics 05/2013; · 7.64 Impact Factor
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International journal of dermatology 04/2013; · 1.18 Impact Factor
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International journal of dermatology 03/2013; · 1.18 Impact Factor
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The Journal of Dermatology 09/2012; 39(9):819-21. · 1.49 Impact Factor
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Kana Kaibuchi-Noda,
Kenji Yokota,
Takaaki Matsumoto,
Masaki Sawada,
Akihiro Sakakibara, Michihiro Kono,
Yasushi Tomita,
Daisuke Watanabe,
Hitomi Fukumoto,
Harutaka Katano,
Masashi Akiyama
Journal of the American Academy of Dermatology 11/2011; 65(5):e152-4. · 3.99 Impact Factor
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ABSTRACT: Interval sentinel lymph nodes (ISLN) are defined as the lymph nodes located between the primary melanoma and anatomically well-defined lymph nodal basins. It was reported that the ISLN appeared to be at the same metastatic risk as sentinel lymph nodes (SLN) in the traditional nodal basins. This study aimed to examine the incidence and metastatic risk of the ISLN in melanoma patients. Between June of 1999 and December of 2008, 117 patients enrolled at Nagoya University Hospital underwent SLN biopsy for primary cutaneous melanoma with a Breslow thickness of at least 1.0 mm. Triple techniques with lymphoscintigraphy, blue dye injection and gamma probe were used for the biopsy except for 13 cases that underwent lymphoscintigraphy, ultrasonography and blue dye injection, but without gamma probe. Patients who had melanoma of the head and neck were excluded from this analysis. The SLN were identified in 253 nodal basins from 117 patients, and ISLN were found in six patients (5%). We recognized 41 (17%) SLN metastases in 246 conventional nodal basins and one (14%) in seven ISLN. Although ISLN were identified infrequently, the incidence of metastasis into the ISLN was similar to that into SLN in conventional nodal basins. It is therefore recommended that preoperative lymphoscintigraphy and intraoperative recognition of ISLN should be performed.
The Journal of Dermatology 07/2010; 37(7):629-34. · 1.49 Impact Factor
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ABSTRACT: Dermoscopic analysis of skin tumor has been mainly focused on pigmented structures. Recently, several different morphological types of vessels were found to be well associated with pigmented or non-pigmented skin tumors in white subjects. Therefore, the recognition of such vascular structures has been applied for diagnostic purposes. As little statistical information on the various pigmented skin tumor vessels of Japanese patients has been reported, we therefore tried to evaluate the association between various vascular structures and 741 tumor lesions of Japanese patients. Vascular structures were dermoscopically recognized in 41 of 102 cases of melanoma, 104 of 119 basal cell carcinoma (BCC), 86 of 257 seborrheic keratosis (SK), 35 of 210 dermal and compound nevus (DN/CN), six of 12 squamous cell carcinoma (SCC) and 16 of 41 Bowen disease (BD). The structures of arborizing and glomerular vessels statistically revealed diagnostic specificity for BCC and BD, respectively, and hairpin vessels were helpful for differentiating SK from other pigmented tumors, as already reported in white patients. The most common vascular pattern observed in melanoma was the linear-irregular structure, but this pattern in Japanese patients had less diagnostic value than in white patients, because its sensitivity was not significantly higher than in SCC. The most remarkable differences between our study and previous reports with white patients were low frequency and sensitivity of dotted, comma and polymorphous vessels in lesions of melanoma, BCC and DN/CN; these vessels had less diagnostic value for Japanese patients. Finally, the frequency of vascular structures observed in melanoma rose along with the increase of the Breslow's tumor thickness, and 88% of melanomas with vascular vessels revealed tumor thicknesses of more than 2 mm.
The Journal of Dermatology 04/2010; 37(4):316-22. · 1.49 Impact Factor
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ABSTRACT: Oculocutaneous albinism type IV (OCA4 [MIM606574]) caused by mutations of the SLC45A2 gene is an autosomal recessive disorder of pigmentation characterized by reduced biosynthesis of melanin pigment in the skin, hair, and eye. We had the opportunity to examine a Belgian boy of Moroccan descent with clinically severe OCA and screened the mutation in his SLC45A2 gene. Sequencing of exon 1, of which the PCR product showed aberrant patterns in the SSCP gel, revealed that the patient was a homozygote for p.H38R mutation. We demonstrated that the p.H38R-mutant protein was functionally incapable of melanin synthesis using melanocyte cultures (under white cells; uw) established from a mouse model of OCA4. This is the second report of the occurrence of OCA4 in a member of an African ethnic group.
American Journal of Medical Genetics Part A 09/2009; 149A(8):1773-6. · 2.39 Impact Factor
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ABSTRACT: Immunotherapy is well-practiced as one of the main adjuvant therapies for melanoma patients. Until now, many immunotherapeutic investigations have focused on improving the effector side of the antitumor response, but only a few studies have been concerned with preventing the loss of tumor-associated antigen (TAA) expression. Loss of TAA should be an important problem for the recognition of tumor cells by cytotoxic T lymphocytes. If any agents that augment the expression of melanoma antigens were found, they could improve the efficacy of immunotherapy by increasing the antigens. To detect effective chemicals, we made a fluorescent cellular reporter system for screening promising candidate chemicals. In this system, the fusion gene of the Melan-A/MART-1 promoter sequence followed by the green fluorescent protein (GFP) coding region was stably transfected into MUX human melanoma cells which are known to express little or no Melan-A/MART-1. Melan-A/MART-1 is a well-known melanoma antigen recognized by autologous cytotoxic T cells, and is a glycoprotein associated with the melanosome, the organelle in which melanin synthesis proceeds. By using this screening system, daunorubicin, doxorubicin and cytochalasin D, which enhanced the green fluorescent, were selected and then were confirmed to actually increase the expression of Melan-A/MART-1 mRNA and protein in human melanoma cells of MU89, MM96L(+) and SK-MEL-28, but also in low-antigen presenting cells such as MM96L(-), MUX, and A375. In conclusion, we have successfully established a well-functioning screening system, which will allow us to find candidate chemicals that up-regulate or maintain the melanoma antigen expression.
The Tohoku Journal of Experimental Medicine 04/2009; 217(3):231-7. · 1.24 Impact Factor
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ABSTRACT: Dyschromatosis symmetrica hereditaria (DSH) is a pigmentary genodermatosis of autosomal dominant inheritance caused by a mutation of adenosine deaminase acting on the RNA 1 gene (ADAR1). It is characterized by a mixture of hyper- and hypopigmented macules on the back of the hands and feet. The pathomechanism by which the ADAR1 gene mutation induces DSH has not been clarified yet. We experienced an 11-year-old male DSH patient associated with dystonia, mental deterioration and brain calcification, who had a mutation of p.G1007R in the ADAR1 gene. This mutation had already been reported in a patient with similar neurological symptoms by Tojo et al. Additionally, a patient with DSH associated with torsion dystonia was reported by Patrizi et al., but gene analysis was not carried out. Only three cases with neurological disorders have been reported, although more than 50 mutations of the ADAR1 gene causing DSH have been reported and none of them had any neurological symptoms. Therefore, we suggest that neurological disorders rarely develop in DSH.
The Journal of Dermatology 11/2008; 35(10):662-6. · 1.49 Impact Factor
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Ichidai Murata,
Yutaka Hozumi,
Masakazu Kawaguchi,
Yoshiyuki Katagiri,
Shinichiro Yasumoto,
Yoshiaki Kubo,
Wataru Fujimoto,
Tatsuya Horikawa,
Taisuke Kondo, Michihiro Kono,
Yasushi Tomita,
Tamio Suzuki
Journal of Dermatological Science 10/2008; 53(1):76-7. · 3.72 Impact Factor
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ABSTRACT: Dyschromatosis symmetrica hereditaria (DSH), is a pigmentary genodermatosis of autosomal dominant inheritance. Since we clarified that the disease is caused by a mutation of the adenosine deaminase acting on the RNA 1 gene (ADAR1) in 2003, the molecular pathogenesis of a peculiar clinical feature of the disease has been expected to be clarified. We examined five familial cases and one sporadic case of Japanese families with DSH. The mutation analyses were done with single-strand conformation polymorphism/heteroduplex (SSCP/HD) analysis and direct sequencing of ADAR1. The DNA analysis of each patient revealed one missense mutation (p.F1091S), two nonsense mutations (p.C893X, p.S581X) and three frame-shift mutations (p.E498fsX517, p.F1091fsX1092, p.L855fsX856). Visual and electron microscopic findings showed abundant melanin pigment deposited all over the basal layer, and enlarged melanocytes with long dendrites located in the pigmented lesions with small or immature melanosomes scattered sparsely in the cytoplasm, but in the adjacent keratinocytes many small melanosomes were singly dispersed or aggregated. The hypopigmented areas showed little melanin deposition and reduced numbers of melanocytes in which much degenerative cytoplasmic vacuole formation could be observed by electron microscopy. Herein, we report six cases of DSH with six novel mutations. The variety of their clinical phenotypes even in the pedigree may suggest the presence of factors other than the ADAR1 gene influencing the extent of the clinical skin lesion. Microscopic findings suggest that the clinical appearance must have developed directly by melanocyte variations mainly induced by the ADAR1 gene mutations.
The Journal of Dermatology 08/2008; 35(7):395-406. · 1.49 Impact Factor
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Noriyuki Suzuki,
Tamio Suzuki,
Katsuhiko Inagaki,
Shiro Ito, Michihiro Kono,
Tatsuya Horikawa,
Sakuhei Fujiwara,
Akira Ishiko,
Kayoko Matsunaga,
Yumi Aoyama,
Hiroko Tosaki-Ichikawa,
Yasushi Tomita
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ABSTRACT: Dyschromatosis symmetrica hereditaria (DSH) is a pigmentary genodermatosis of autosomal-dominant inheritance. We have reported 20 different mutations of the adenosine deaminase acting on RNA 1 gene (ADAR1) in patients with DSH since we had clarified that the disease is caused by a mutation of the ADAR1 gene in 2003. In this study, we report 10 novel mutations responsible for DSH: p.Q102fsX123, p.T369fsX374, p.S664fsX677, p.R892L, p.I913R, p.R916Q, p.P990fsX1016, p.C1081S, p.C1169F, and p.K1187X.
Journal of Investigative Dermatology 03/2007; 127(2):309-11. · 6.31 Impact Factor
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Journal of Dermatological Science 12/2006; 44(2):116-8. · 3.72 Impact Factor
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Katsuhiko Inagaki,
Tamio Suzuki,
Shiro Ito,
Noriyuki Suzuki,
Koji Adachi,
Torayuki Okuyama,
Yusei Nakata,
Hiroshi Shimizu,
Hironori Matsuura,
Takashi Oono,
Hiroko Iwamatsu, Michihiro Kono,
Yasushi Tomita
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ABSTRACT: Oculocutaneous albinism type 4 (OCA4) is an autosomal recessive hypopigmentary disorder caused by mutations in the Membrane-Associated Transporter Protein gene (SLC45A2). The SLC45A2 protein is a 530-amino-acid polypeptide that contains 12 putative transmembrane domains, and appears to be a transporter that mediates melanin synthesis. Eighteen pathological mutations have been reported so far. In this study, six novel mutations, p.Y49C (c.146A > G), p.G89R (c.265G > A), p.C229Y (c.686G > A), p.T437A (c.1309A > G), p.T440A (c.1318A > G) and p.G473D (c.1418G > A) were found in eight Japanese patients with various clinical phenotypes. The phenotypes of OCA4 were as various as the other types of OCA and probably depended on the mutation sites in the SLC45A2 gene.
Pigment Cell Research 10/2006; 19(5):451-3. · 4.29 Impact Factor
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ABSTRACT: Many mutations of the tyrosinase gene have been reported in oculocutaneous albinism type I (OCA1) patient. In the future, a greater number of novel mutations will be found as the search for pathological mutations in the tyrosinase genes of OCA patients from various ethnic origins. For rapid determination in future whether an observed mutation is a polymorphism or a novel pathological one, sequence databases of the gene of various ethnic people are needed.
We established a sequence database of the tyrosinase gene of Japanese as well as Indian people.
We collected DNA from 109 Japanese and 103 Indians with normal pigmentation and analyzed their tyrosinase gene using a direct sequencing method.
The database shows an apparent difference between the two ethnic groups in polymorphisms of the tyrosinase gene namely, Q402 allele, Y192 allele and IV2+24 insT were found in the Indian population, but not in the Japanese. On the other hand, some Japanese had IV2-21 insT but none of the Indians did. The database supports the notion that the tyrosinase gene evolved and extended separately in the two ethnic groups. And the developing database confirmed that the reported mutations causing Indian and Japanese OCA were not among the polymorphisms in the database, which conversely gives genetical proof of the "genuine" pathological mutations.
Eventually, the sequence database we established will contribute to demonstrating novel mutations of albinism in Indians and Japanese.
Journal of Dermatological Science 10/2005; 39(3):167-73. · 3.72 Impact Factor
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Yoshinori Miyamura,
Ishwar C Verma,
Renu Saxena,
Michiko Hoshi,
Ayumi Murase,
Eriko Nakamura, Michihiro Kono,
Tamio Suzuki,
Satoshi Yasue,
Shin-Ichi Shibata,
Akihiro Sakakibara,
Yasushi Tomita
Journal of Investigative Dermatology 09/2005; 125(2):397-8. · 6.31 Impact Factor
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Noriyuki Suzuki,
Tamio Suzuki,
Katsuhiko Inagaki,
Shiro Ito, Michihiro Kono,
Kazuyoshi Fukai,
Hiromichi Takama,
Kenji Sato,
Osamu Ishikawa,
Masatoshi Abe,
Hiroshi Shimizu,
Masaaki Kawai,
Tatsuya Horikawa,
Kunihiro Yoshida,
Kazuhiko Matsumoto,
Tadashi Terui,
Kaoru Tsujioka,
Yasushi Tomita
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ABSTRACT: Dyschromatosis symmetrica hereditaria (DSH) (also called "reticulate acropigmentation of Dohi") is a pigmentary genodermatosis of autosomal dominant inheritance. We have clarified for the first time four pathological mutations of the double-stranded RNA-specific adenosine deaminase gene (ADAR1 or DSRAD) in four DSH pedigrees. In this paper, we report 16 novel mutations containing six missense substitutions (p.V906F, p.K1003R, p.G1007R, p.C1036S, p.S1064F, p.R1078C), two splice site mutations (IVS2+2T>G, IVS8+2T>A), six frameshift mutations (p.H216fs, p.K433fs, p.G507fs, p.P727fs, p.V955fs, p.K1201fs), and two nonsense mutations (p.R426X, p.Q600X) found in Japanese patients with DSH. We did not establish any clear correlation between the clinical phenotypes and the genotypes of ADAR1 gene mutations in our examination of 16 cases plus four pedigrees. None of the different mutations identified in our studies of 20 cases suggested any founder effect. Furthermore, we did not identify any mutations in the ADAR1 gene of three patients with dyschromatosis universalis hereditaria or three patients with acropigmentatio reticularis, indicating that the two diseases are completely different from DSH, although they have sometimes been suggested to be phenotypical variations of DSH.
Journal of Investigative Dermatology 07/2005; 124(6):1186-92. · 6.31 Impact Factor
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ABSTRACT: The molecular bases of various types of congenital hypopigmentary disorders have been clarified in the past 10 years. Homozygous gene mutations of enzymes functional in melanogenesis such as tyrosinase, P protein and DHICA oxidase, result in oculocutaneous albinism (OCA) 1, OCA 2, and OCA 3, respectively. The genes responsible for Hermansky-Pudlak syndrome (HPS) and Chediak-Higashi syndrome (CHS) have also recently been isolated and cloned. The transcription factor paired box 3 (PAX3) works at the promoter region of the microphthalmia-associated transcription factor (MITF) gene, and the MITF transcription factor orders the expression of c-kit, which encodes the receptor for stem-cell factor, which in turn stimulates melanoblast migration from the neural tube to the skin in the embryo. Heterozygous mutations of PAX3, MITF, or c-kit genes induce Waardenburg syndrome (WS) 1/3, WS 2 or Piebaldism, respectively. A defect of endothelin-3 or the endothelin-B receptor produces WS 4. In our examination of 26 OCA 1 patients in Japan, all were found to have homozygous or heterozygous tyrosinase gene mutations at codons 77 or 310. Therefore, mutations at codons 77 and 310 are the major ones in Japanese patients with OCA 1. An autosomal dominant pigmentary disease of dyschromatosis symmetrica hereditaria (DSH) is well known in Japan, and is characterized by a mixture of hypo- and hyper-pigmented macules of various sizes on the backs of the hands and feet. The disease gene and its chromosomal localization have not been identified yet. Our trial of linkage analysis and positional cloning to determine the disease gene is presented.
Pigment Cell Research 12/2003; 13(s8):130 - 134. · 4.29 Impact Factor
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ABSTRACT: Dyschromatosis symmetrica hereditaria (DSH) (also called "reticulate acropigmentation of Dohi") is a pigmentary genodermatosis of autosomal dominant inheritance characterized by a mixture of hyperpigmented and hypopigmented macules distributed on the dorsal aspects of the hands and feet. To determine the gene responsible for this disease, we performed a genomewide search in three families with DSH and mapped the DSH locus to chromosome 1q21.3. The mutations involved in causing DSH have been identified in the gene that encodes double-stranded RNA-specific adenosine deaminase (DSRAD) as the disease gene.
The American Journal of Human Genetics 10/2003; 73(3):693-9. · 10.60 Impact Factor
