Dyschromatosis symmetrica hereditaria associated with neurological disorders.

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.

Six novel mutations of the ADAR1 gene in patients with dyschromatosis symmetrica hereditaria: histological observation and comparison of genotypes and clinical phenotypes.

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.

Ten novel mutations of the ADAR1 gene in Japanese patients with dyschromatosis symmetrica hereditaria.

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.

Virus-like particles associated with mass mortalities of the pen shell Atrina pectinata in Japan.

Mass mortalities of the pen shell Atrina pectinata occurred in the fishing grounds of Ariake Bay, in southwestern Japan, during late spring and summer in 2003 and 2004. Histological examination revealed extensive necrosis in the epithelial cells of the kidney and gill, and impairment of the endothelial cells of the mantle arteria. Although cestode larvae belonging to the genus Tylocephalum were found in the mantle, adductor muscle, kidney, and digestive gland, their prevalence and the intensity of infection were low. Examinations of moribund pen shells for Haplosporidium spp. infection using PCR analysis and for Perkinsus spp. infection using Ray's fluid thioglycollate medium were negative. Unenveloped virus-like particles were detected by transmission electron microscopy in the cytoplasm of affected kidney and gill cells of moribund pen shells. They were icosahedral spherical and 50 to 55 nm in diameter. These virus-like particles found in moribund pen shells are different from those described in other marine mollusks, and may be the causative agent of the mass mortalities of pen shells.

Oculocutaneous albinism type 4: six novel mutations in the membrane-associated transporter protein gene and their phenotypes.

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.

High frequency of Hermansky-Pudlak syndrome type 1 (HPS1) among Japanese albinism patients and functional analysis of HPS1 mutant protein.

Hermansky-Pudlak syndrome (HPS) is an autosomal recessive disorder characterized by oculocutaneous albinism (OCA), bleeding tendency, and lysosomal accumulation of ceroid-like material. Seven genetically distinct subtypes of HPS are known in humans; most are rare outside of Puerto Rico. Here, we describe the analysis of the HPS1 gene in 24 Japanese OCA patients who lacked mutations in the four genes known to cause OCA (TYR/OCA1, P/OCA2, TYRP1/OCA3, and MATP/OCA4), and the identification of eight different HPS1 mutations in ten of these patients, four of which were novel (W583X, L668P, 532insC, 1691delA). An IVS5+5G --> A splice consensus mutation was particularly frequent, the result of a founder effect for this allele in Japanese patients. Functional analysis by transfection of the L668P variant into Hps1-mutant melan-ep mouse melanocytes showed that this missense substitution is pathologic, resulting in an Hps-1 protein that is unable to assemble into the biogenesis of lysosome-related organelles complex-3.

OCA4: evidence for a founder effect for the p.D157N mutation of the MATP gene in Japanese and Korean.

Oculocutaneous albinism type 4 (OCA4) was identified as a rare form of human OCA among a group of autosomal recessive hypopigmentary disorders. Little is known about the prevailing distribution of patients of OCA4 with mutations of the MATP gene, although one Turkish, five German, one Korean, and 18 Japanese patients have been reported so far. The p.D157N mutation was previously reported to be the most frequent (0.389; 14/36) in Japanese patients and was also found in a Korean patient. On the other hand, this mutation has not been found in Turkish and German patients. We therefore investigated haplotypes of the patients who have the p.D157N mutation. The results showed that OCA4 is prevalent in East Asia including Japan and Korea likely as a result of a founder effect for the p.D157N mutation. Furthermore, it is suspected that the p.D157N mutation might have occurred on an ancestral chromosome after the divergence of Orientals and Caucasians.

[Medical pots of Yakushi Buddha in Japan]. / Les pots de médicament de Yakushi Bouddha (bouddha de la guérison) au Japon.

The origin of Yakushi buddha (Bhaisajyaguru in Sanscrit, buddha of healing) is not clearly known. It has been proposed the original statue of Yakushi buddha may have been conceived from Varna, a god in Brahminism, believed to be a god of justice who possessed medicines and prolonged life. It is believed that Yakushi buddha appeared in Japan when the buddhism was imported from Korea and China in VI century, Yakushi buddha was believed more profoundly in Japan, compared with Korea and China.The reasons are probably as follows: Yakushi buddha is buddha of healing, Emperor Temmu (672-685) built Yakushi-ji temple in Nara, Emperor Shomu (724-749) built Kokubun-ji temples at principal towns. The principal statues of buddha in these temples are Yakushi buddha. In Japan, there are 252 Yakushi Buddha statues in Buddhistical Temples, which are listed in Important Cultural Property including 14 National Treasures. Belief in Yakushi Buddha was especially prevalent from the 7th to the 13th centuries in Japan. The oldest wooden Yakushi Buddha statue is in the Horin-ji temple in Nara. Among the 252 Yakushi Buddha statues, 224 are in wood, 15 are in copper, 6 are in picture and etc. 212 (84,1%) have medicinal pots (or rarely, a bowl) on the palm of left hand. However, these medicinal containers are wooden blocks. Very recently, it was found that Yakushi Buddha statue in the Suho-Kokubun-ji temple (Yamaguchi Prefecture, Japan) has a medicinal pot on the palm of the left hand in which an offering (220 g materials) was found. The date on the reverse side of lid places the offering at October 12, 1699. The offering is composed of five cereals (rice, barley, wheat, soybean, adzuki bean), five medicinal plants (Acori Graminei, Acori Calami, Radix Ginseng, Flos Caryophylli, Lignum Santali Albi), and five minerals (rock crystals, purple and blue glasse, CaCO3, particles, silver and golden foils). DNA analysis proved those three randomly selected seeds of rice all belongs to the template japonica, which is predominant in the present variety of Japan.

Ultrastructural features of trafficking defects are pronounced in melanocytic nevus in Hermansky-Pudlak syndrome type 1.

Hermansky-Pudlak syndrome (HPS) is an autosomal recessive disorder characterized by oculocutaneous albinism, a bleeding disorder, and ceroid lipofuscinosis in the lungs and gut. HPS is genetically heterogeneous and the most common variant, HPS type 1, is caused by mutations in HPS1 gene. The protein encoded by HPS1 is considered to facilitate the trafficking of melanocyte-specific gene products into the premelanosome. We report the ultrastructural findings in a melanocytic nevus seen in a 17-y-old Japanese female patient with HPS1 who is a compound heterozygote of HPS1 mutations, including a novel mutation. Electron microscopy of a pinkish papule corresponding to the melanocytic nevus revealed markedly aberrant, immature melanosomes, large membranous structures, and giant melanosomes in the vicinity of trans-Golgi network, the characteristic abnormalities because of protein trafficking defects in HPS1. These ultrastructural features were far more clearly demonstrated in the nevus cells than in the epidermal melanocytes. Thus, ultrastructural analysis of nevus cells may be an additional diagnostic tool for HPS1 and could give us important clues to further understanding of the pathomechanisms of HPS.

Mutation analysis of the ADAR1 gene in dyschromatosis symmetrica hereditaria and genetic differentiation from both dyschromatosis universalis hereditaria and acropigmentatio reticularis.

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.

A patient with subclinical oculocutaneous albinism type 2 diagnosed on getting severely sunburned.

P-gene-related oculocutaneous albinism (OCA2) is an autosomal recessive disorder. The phenotype is typically somewhat less severe than that of the tyrosinase-negative type (OCA1A). One of the mutations in the P gene, A481T, is associated with a mild phenotype, occasionally with no distinctive skin manifestations, which is called subclinical OCA. We present a Japanese patient having the A481T mutant allele in the P gene with subclinical oculocutaneous albinism diagnosed on getting severely sunburned. The A481T mutant allele is relatively common in the Caucasian population as well as in Japan, indicating that a number of subclinical patients of OCA2 might exist not only in Japan, but also all over the world.

Oculocutaneous albinism type 4 is one of the most common types of albinism in Japan.

Oculocutaneous albinism (OCA) is a complex genetic disease with great clinical heterogeneity. Four different types of OCA have been reported to date (OCA1, OCA2, OCA3, and OCA4). MATP was recently reported in a single Turkish OCA patient as the fourth pathological gene, but no other patients with OCA4 have been reported. Here, we report the mutational profile of OCA4, determined by genetic analysis of the MATP gene in a large Japanese population with OCA. Of 75 unrelated patients that were screened, 18 individuals (24%) were identified as having OCA4; they harbored seven novel mutations, including four missense mutations (P58S, D157N, G188V, and V507L) and three frameshift mutations (S90CGGCCA-->GC, V144insAAGT, and V469delG), showing that MATP is the most frequent locus for tyrosinase-positive OCA in Japanese patients. We discuss the functional melanogenic activity of each mutant allele, judging from the relationship between the phenotypes and genotypes of the patients. This is the first report on a large group of patients with OCA4.

Mutations of the RNA-specific adenosine deaminase gene (DSRAD) are involved in dyschromatosis symmetrica hereditaria.

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.