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Chinen, Yasutsugu ; Yanagi, Kumiko ; Nakamura, Sadao ; Nakayama, Noriko ; Kamiya, Motoko ; Nakayashiro, Mami ; Kaname, Tadashi ; Naritomi, Kenji ; Nakanishi, Koichi
出版情報: Human Genome Variation.  7  2020-04-16.  Springer Nature
URL: http://hdl.handle.net/20.500.12000/47023
概要: Carnitine-acylcarnitine translocase (CACT) deficiency is a fatty acid ß-oxidation disorder of the carnitine shuttle in m itochondria, with a high mortality rate in childhood. We evaluated three patients, including two siblings, with neonatal-onset CACT deficiency and revealed identical homozygous missense mutations of p.Arg275Gln within the SLC25A20 gene. One patient died from hypoglycemia and arrhythmia at 26 months; his pathological autopsy revealed increased and enlarged mitochondria in the heart but not in the liver.
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2.

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Yonamine, Tomoko ; Kaname, Tadashi ; Chinen, Yasutsugu ; Tamashiro, Kouichi ; Kosuge, Noritake ; Saito, Seiichi
出版情報: Urology Case Reports.  30  2020-05.  Elsevier
URL: http://hdl.handle.net/20.500.12000/47486
概要: Hereditary leiomyomatosis and renal cell cancer is a rare, inherited disease caused by mutations in the fumarate hydrata se gene. It is characterized by cutaneous leiomyomas, uterine leiomyomas, and/or renal cell cancer. We present the case of a 42-year-old woman with a heterozygous missense mutation (p.M195T) in the fumarate hydratase gene. Although the patient did not have cutaneous leiomyoma and she had no family history of hereditary leiomyomatosis and renal cell cancer, the presence of early onset symptomatic uterine leiomyoma and type 2 papillary renal cell cancer confirmed the diagnosis of hereditary leiomyomatosis and renal cell cancer.
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3.

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Chinen, Yasutsugu ; Nakamura, Sadao ; Kaneshi, Takuya ; Nakayashiro, Mami ; Yanagi, Kumiko ; Kaname, Tadashi ; Naritomi, Kenji ; Nakanishi, Koichi
出版情報: Human Genome Variation.  6  2019-05-13.  Springer Nature
URL: http://hdl.handle.net/20.500.12000/45906
概要: Cornelia de Lange syndrome (CdLS) is a cohesinopathy caused by genetic variations. We present a female with SMC1A-associ ated CdLS with a novel SMC1A truncation mutation (p. Arg499Ter), transposition of the great arteries, and periodic intractable seizures from 40 months of age. A review of the literature revealed that a seizure-free period after birth of at least 15 months is required for these patients to be able to walk, irrespective of the epileptic course.
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4.

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Hayashi, Shin ; Uehara, Daniela Tiaki ; Tanimoto, Kousuke ; Mizuno, Seiji ; Chinen, Yasutsugu ; Fukumura, Shinobu ; Takanashi, Jun-ichi ; Osaka, Hitoshi ; Okamoto, Nobuhiko ; Inazawa, Johji
出版情報: PLOS ONE.  12  2018-06-14.  Public Library of Science
URL: http://hdl.handle.net/20.500.12000/45639
概要: The CASK gene (Xp11.4) is highly expressed in the mammalian nervous system and plays several roles in neural development and synaptic function. Loss-of-function mutations of CASK are associated with intellectual disability and microcephaly with pontine and cerebellar hypoplasia (MICPCH), especially in females. Here, we present a comprehensive investigation of 41 MICPCH patients, analyzed by mutational search of CASK and screening of candidate genes using an SNP array, targeted resequencing and whole-exome sequencing (WES). In total, we identified causative or candidate genomic aberrations in 37 of the 41 cases (90.2%). CASK aberrations including a rare mosaic mutation in a male patient, were found in 32 cases, and a mutation in ITPR1, another known gene in which mutations are causative for MICPCH, was found in one case. We also found aberrations involving genes other than CASK, such as HDAC2, MARCKS, and possibly HS3ST5, which may be associated with MICPCH. Moreover, the targeted resequencing screening detected heterozygous variants in RELN in two cases, of uncertain pathogenicity, and WES analysis suggested that concurrent mutations of both DYNC1H1 and DCTN1 in one case could lead to MICPCH. Our results not only identified the etiology of MICPCH in nearly all the investigated patients but also suggest that MICPCH is a genetically heterogeneous condition, in which CASK inactivating mutations appear to account for the majority of cases.
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5.

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Chinen, Yasutsugu ; Nakamura, Sadao ; Ganaha, Akira ; Hayashi, Shin ; Inazawa, Johji ; Yanagi, Kumiko ; Nakanishi, Koichi ; Kaname, Tadashi ; Naritomi, Kenji
出版情報: Clinical Case Reports.  6  pp.330-336,  2018-02.  Wiley
URL: http://hdl.handle.net/20.500.12000/45875
概要: A Japanese boy aged 7 years with Bainbridge-Ropers syndrome (BRPS) had a prominent domed forehead without metric ridge, mild prominence of the Sylvian fissure with bitemporal hollowing, and a heterozygous de novo novel variant "p.P1010Lfs*14" in ASXL3 gene in addition to typical findings of BRPS.
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6.

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Chinen, Yasutsugu ; Nakamura, Sadao ; Yoshida, Tomohide ; Maruyama, Hiroki ; Nakamura, Kimitoshi
出版情報: Human Genome Variation.  4  2017-02-16.  Springer Nature
URL: http://hdl.handle.net/20.500.12000/45907
概要: A pilot study of newborn screening for Fabry disease was performed in Okinawa, Japan. A total of 2,443 neonates were scr eened using dried blood spot samples over 7 years starting in 2007. Of 13 neonates determined to have low alpha-galactosidase A (GLA) activity, one boy had a new missense mutation, p.G144D of the GLA gene. This mutation was considered to be a late-onset type, as evaluated based on plasma globotriaosylsphingosine levels and family history.
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7.

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Chinen, Yasutsugu ; Nakamura, Sadao ; Tamashiro, Kunihito ; Sakamoto, Osamu ; Tashiro, Kyoko ; Inokuchi, Takahiro ; Nakanishi, Koichi
出版情報: Molecular Genetics and Metabolism Reports.  11  pp.2-5,  2017-06.  Elsevier
URL: http://hdl.handle.net/20.500.12000/45971
概要: Isovaleric acidemia (IVA) is an organic acid disease caused by a deficiency of isovaleryl-CoA dehydrogenase. Deficiency of this enzyme leads to accumulation of organic acids, such as isovalerylcarnitine and isovalerylglycine. The proposed IVA treatments include leucine restriction and l-carnitine and/or glycine supplementation, which convert isovaleric acid into non-toxic isovalerylcarnitine and isovalerylglycine, respectively. We examined the therapeutic response using the leucine load test and performed a 10-year follow-up in the patient. Methods:We evaluated the patient with IVA beginning at 5 years of age, when he presented with a mild to intermediate metabolic phenotype. Ammonia, free carnitine, isovalerylcarnitine, and isovalerylglycine were analyzed in the urine and blood after a meal consisting of 1600 mg leucine with glycine alone (250 mg/kg/day), l-carnitine alone (100 mg/kg/day), or both glycine and l-carnitine for four days each. Results:(Leucine load test) Three hours after the meal, serum ammonia levels increased most dramatically with glycine treatment alone, then with both in combination, and least with l-carnitine alone. Urinary isovalerylglycine levels increased 2-fold more with glycine supplementation than those following supplementation with both agents or with l-carnitine alone. Treatment with both agents resulted in a gradual increase in urinary acylcarnitine levels during the 6-h period following the leucine load, reaching concentrations comparable to those observed with l-carnitine alone. (Clinical course) After initiation of both glycine (200 mg/kg/day) and l-carnitine (100 mg/kg/day) supplementation at 5 years of age, doses were gradually reduced to 111.7 mg/kg/day and 55.8 mg/kg/day, respectively, at 15 years of age. His mind and body had developed without any sequelae. Discussion:We concluded that l-carnitine conjugated isovaleric acid earlier than glycine. Additionally, during the 10-year follow-up period, the patient displayed no clinical deterioration.
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8.

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Tomatsu, Shunji ; Sawamoto, Kazuki ; Almeciga-Diaz, Carlos J. ; Shimada, Tsutomu ; Bober, Michael B. ; Chinen, Yasutsugu ; Yabe, Hiromasa ; Montano, Adriana M. ; Giugliani, Roberto ; Kubaski, Francyne ; Yasuda, Eriko ; Rodriguez-Lopez, Alexander ; Espejp-Mojica, Angela J. ; Sanchez, Oscar F. ; Mason, Robert W. ; Barrera, Luis A. ; Mackenize, William G. ; Orii, Tadao
出版情報: Drug Design, Development and Therapy.  9  pp.1937-1953,  2015-04-01.  Dove Medical Press
URL: http://hdl.handle.net/20.500.12000/45879
概要: Patients with mucopolysaccharidosis IVA (MPS IVA) can present with systemic skeletal dysplasia, leading to a need for mu ltiple orthopedic surgical procedures, and often become wheelchair bound in their teenage years. Studies on patients with MPS IVA treated by enzyme replacement therapy (ERT) showed a sharp reduction on urinary keratan sulfate, but only modest improvement based on a 6-minute walk test and no significant improvement on a 3-minute climb-up test and lung function test compared with the placebo group, at least in the short-term. Surgical remnants from ERT-treated patients did not show reduction of storage materials in chondrocytes. The impact of ERT on bone lesions in patients with MPS IVA remains limited. ERT seems to be enhanced in a mouse model of MPS IVA by a novel form of the enzyme tagged with a bone-targeting moiety. The tagged enzyme remained in the circulation much longer than untagged native enzyme and was delivered to and retained in bone. Three-month- old MPS IVA mice treated with 23 weekly infusions of tagged enzyme showed marked clearance of the storage materials in bone, bone marrow, and heart valves. When treatment was initiated at birth, reduction of storage materials in tissues was even greater. These findings indicate that specific targeting of the enzyme to bone at an early stage may improve efficacy of ERT for MPS IVA. Recombinant N-acetylgalactosamine-6-sulfate sulfatase (GALNS) in Escherichia coli BL21 (DE3) (erGALNS) and in the methylotrophic yeast Pichia pastoris (prGALNS) has been produced as an alternative to the conventional production in Chinese hamster ovary cells. Recombinant GALNS produced in microorganisms may help to reduce the high cost of ERT and the introduction of modifications to enhance targeting. Although only a limited number of patients with MPS IVA have been treated with hematopoietic stem cell transplantation (HSCT), beneficial effects have been reported. A wheelchair-bound patient with a severe form of MPS IVA was treated with HSCT at 15 years of age and followed up for 10 years. Radiographs showed that the figures of major and minor trochanter appeared. Loud snoring and apnea disappeared. In all, 1 year after bone marrow transplantation, bone mineral density at L2-L4 was increased from 0.372 g/cm(2) to 0.548 g/cm(2) and was maintained at a level of 0.48 +/- 0.054 for the following 9 years. Pulmonary vital capacity increased approximately 20% from a baseline of 1.08 L to around 1.31 L over the first 2 years and was maintained thereafter. Activity of daily living was improved similar to the normal control group. After bilateral osteotomies, a patient can walk over 400 m using hip-knee-ankle-foot orthoses. This long-term observation of a patient shows that this treatment can produce clinical improvements although bone deformity remained unchanged. In conclusion, ERT is a therapeutic option for MPS IVA patients, and there are some indications that HSCT may be an alternative to treat this disease. However, as neither seems to be a curative therapy, at least for the skeletal dysplasia in MPS IVA patients, new approaches are investigated to enhance efficacy and reduce costs to benefit MPS IVA patients.
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9.

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Yanagi, Kumiko ; Kaname, Tadashi ; Chinen, Yasutsugu ; Naritomi, Kenji
出版情報: 琉球医学会誌 = Ryukyu Medical Journal.  23  pp.143-148,  琉球医学会 — Ryukyu Medical Association
概要: Faciogenital dysplasia 1 (FGD1) gene has been identified as a responsible gene for Aarskog-Scott syndrome (AAS). We char acterized two novel point mutations in two Japanese families with AAS, a missense mutation in exon 11 (1906C>T, R636W) and a nucleotide transition at the first position of the 5' splice donor site of intron 14 (IVS14+1G>A). The missense mutation probably results in reduced FGD1 function and the mutation at the splice donor site decreases FGDl gene expression. These mutations were identified by sequencing and were confirmed by allele-specific polymerase chain reaction (AS-PCR) or by PCR-restriction fragment length polymorphism (PCR-RFLP). The mutations were absent in twenty-five Japanese control subjects, which supports the notion that these mutations result in AAS. This study represents the first mutational analysis of FGD1 in Japanese AAS patients.
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