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1.
J Clin Immunol ; 43(8): 2115-2125, 2023 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-37770806

RESUMO

Biallelic KARS1 mutations cause KARS-related diseases, a rare syndromic condition encompassing central and peripheral nervous system impairment, heart and liver disease, and deafness. KARS1 encodes the t-RNA synthase of lysine, an aminoacyl-tRNA synthetase, involved in different physiological mechanisms (such as angiogenesis, post-translational modifications, translation initiation, autophagy and mitochondrial function). Although patients with immune-hematological abnormalities have been individually described, results have not been collectively discussed and functional studies investigating how KARS1 mutations affect B cells have not been performed. Here, we describe one patient with severe developmental delay, sensoneurinal deafness, acute disseminated encephalomyelitis, hypogammaglobulinemia and recurrent infections. Pathogenic biallelic KARS1 variants (Phe291Val/ Pro499Leu) were associated with impaired B cell metabolism (decreased mitochondrial numbers and activity). All published cases of KARS-related diseases were identified. The corresponding authors and researchers involved in the diagnosis of inborn errors of immunity or genetic syndromes were contacted to obtain up-to-date clinical and immunological information. Seventeen patients with KARS-related diseases were identified. Recurrent/severe infections (9/17) and B cell abnormalities (either B cell lymphopenia [3/9], hypogammaglobulinemia [either IgG, IgA or IgM; 6/15] or impaired vaccine responses [4/7]) were frequently reported. Immunoglobulin replacement therapy was given in five patients. Full immunological assessment is warranted in these patients, who may require detailed investigation and specific supportive treatment.


Assuntos
Agamaglobulinemia , Aminoacil-tRNA Sintetases , Lisina-tRNA Ligase , Doenças da Imunodeficiência Primária , Humanos , Agamaglobulinemia/diagnóstico , Agamaglobulinemia/genética , Aminoacil-tRNA Sintetases/genética , Aminoacil-tRNA Sintetases/metabolismo , Surdez/genética , Lisina-tRNA Ligase/genética , Lisina-tRNA Ligase/metabolismo , Mutação/genética , Doenças da Imunodeficiência Primária/genética
2.
Pediatr Int ; 61(2): 180-189, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30548979

RESUMO

BACKGROUND: Mucopolysaccharidosis (MPS) VI is a rare, autosomal recessive congenital metabolic disorder caused by deficient activity of the lysosomal metabolic enzyme, N-acetylgalactosamine 4-sulfatase. Enzyme replacement therapy (ERT) is the current treatment for MPS VI, although it involves limited compliance to the therapy and high cost. The aim of this study was to develop a new method of treatment by conducting an orthotopic liver transplantation (LTx) using an animal model of human MPS VI, and to evaluate and examine its effectiveness for treating MPS VI. METHODS: LTx was carried out from normal unaffected to affected MPS VI rats (MPR), which were then killed after LTx, and tissues from the heart, spleen, and knee joint, as well as serum, collected for biological and morphologic evaluation. RESULTS: Liver-transplanted (LTx) MPR had the same level of N-acetylgalactosamine 4-sulfatase activity in the liver and lungs as normal unaffected MPR, and the urinary secretion of mucopolysaccharides/glycosaminoglycan (GAG) in LTx MPR was significantly decreased. Furthermore, on histopathology, the spleens of LTx MPR showed elimination of vacuole cells. In the knee joints, growth plates became thinner, and on radiography the facial and cranial bones of LTx MPR were morphologically normal. CONCLUSIONS: LTx from normal to affected MPR was effective for symptoms of MPS and accumulation of GAG, suggesting that LTx could be a promising alternative approach for MPS VI.


Assuntos
Transplante de Fígado , Mucopolissacaridose VI/cirurgia , Animais , Ratos , Ratos Wistar , Resultado do Tratamento
5.
Hum Genome Var ; 9(1): 32, 2022 Sep 12.
Artigo em Inglês | MEDLINE | ID: mdl-36097158

RESUMO

We describe a patient presenting with argininosuccinic aciduria and Silver-Russell syndrome (SRS). SRS was caused by maternal uniparental disomy of chromosome 7 (UPD(7)mat). UPD(7)mat also unmasked a maternally inherited splicing variant in ASL on chromosome 7, leading to the onset of argininosuccinic aciduria. The phenotype of the present case was more severe than that of a previous case, demonstrating a phenotypic variation in the combination of argininosuccinic aciduria and SRS.

6.
Mol Genet Metab Rep ; 24: 100630, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32775211

RESUMO

The natural history of cognitive growth in the neuronopathic form of Mucopolysaccharidosis type II (MPS II) is not well defined especially their patterns of development and decline. The ability to predict the developmental course of the neurologically impaired patient is necessary to assess treatment outcomes aimed at the brain. Thirteen intravenous enzyme replacement therapy-treated Japanese patients with neuronopathic MPSII who had mutation analysis were followed on one standard measure of cognitive development over time. Six children in Group MS had missense mutations and 7 children in Group NT had null type mutations such as deletions, recombination with the pseudogene, and nonsense mutations. The patients as a whole demonstrated cognitive growth until about 36-42 months of age, followed by a plateau in development. The mean age equivalent score at age 3 was similar to that at age 6. While the decline was slow for the entire group, the patients in Group NT showed a more rapid decline than those in Group MS. Two patients with deletions showed decline to a very low level by age 5. The long plateau in cognitive development in patents with MPS II was substantiated and was consistent with other studies. This is the first demonstration that different mutation types within the neuronopathic MPS II patients are associated with different rates of decline. We also were able to identify the chronological age before which a trial would need to start in order to maintain cognitive growth and a ceiling beyond which a relatively normal outcome would not be likely.

7.
Mol Genet Metab Rep ; 25: 100692, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33335838

RESUMO

We previously showed that the genotype-phenotype correlation in MPS II is well-conserved in Japan (Kosuga et al., 2016). Almost all of our patients with attenuated MPS II have missense variants, which is expected to result in residual activity of iduronate-2-sulfatase. In contrast, our patients with severe MPS II have so-called null-type disease-associated variants, such as nonsense variants, frame-shifts, gene insertions, gene deletions and rearrangement with pseudogene (IDS2), none of which are expected to result in residual activity. However, we recently encountered a patient with attenuated MPS II who had a presumable null-type disease-associated variant and 76-base deletion located in exon 1 that extended into intron 1. To investigate this discordance, we extracted RNA from the leukocytes of the patient and performed reverse transcription polymerase chain reaction. One of the bands of the cDNA analysis was found to include a nucleotide sequence whose transcript was expected to generate an almost full-length IDS mature peptide lacking only part of its signal peptide as well as only one amino acid at the end of the N-terminus. This suggests that an alternative splicing donor site is generated in exon 1 upstream of the deleted region. Based on these observations, we concluded that the phenotype-genotype discordance in this patient with MPS II was due to the decreased amount of IDS protein induced by the low level of the alternatively spliced mRNA, lacking part of the region coding for the signal peptide but including the region coding almost the full mature IDS protein. The first 25 amino acids at the N-terminus of IDS protein are a signal peptide. The alternative splice transcript has only 13 (1 M-13 L) of those 25 amino acids; 14G-25G are missing, suggesting that the exclusively hydrophobic 1 M-13 L of the signal peptide of IDS might have a crucial role in the signal peptide.

8.
Hum Genome Var ; 6: 56, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31934343

RESUMO

Autosomal recessive primary microcephaly 5 (MCPH5) is caused by pathogenic variants in ASPM. Using whole-exome sequencing, we diagnosed two siblings with MCPH5. A known pathogenic variant (NM_018136.4: c.9697C > T, p.(Arg3233*)) and a novel pathogenic variant (c.1402_1406del, p.(Asn468Serfs*2)) of ASPM were identified in affected siblings with normal intelligence. Their pathogenic variants were not located in the critical regions of ASPM, but the relationship between the genotypes and their normal intelligence was unclear.

9.
Brain Dev ; 41(6): 546-550, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30755342

RESUMO

Mucopolysaccharidosis type IH (MPS IH, Hurler syndrome) is a progressive, multisystem autosomal recessive lysosomal storage disorder resulting in the consequent accumulation of glycosaminoglycans. It is well recognized that early hematopoietic stem cell transplantation (HSCT) prevents neurocognitive decline in MPS IH. We followed the divergent clinical course in two Japanese siblings with MPS IH. The elder sister (proband) received a diagnosis of MPS IH at 6 months old. At the time of this diagnosis enzyme replacement therapy (ERT) was not available in Japan. She developed severe and recurrent respiratory disease and died at 1 year 10 months of age. Her younger sister also received a diagnosis of MPS IH, but at 18 days of age, and started ERT at 34 days of age. ERT continued until 8 months of age and prevented the progression of somatic manifestations of MPS IH. She received HSCT at 9 months old. Five years after HSCT she had no symptoms of MPS IH except for mild signs of dysostosis multiplex and mild cardiac valvular disease. Her neurological function was generally preserved compared with her elder sister. The prognosis and quality of life differed significantly between the sisters. Therefore, early HSCT can preserve neurocognition by preventing the neurodegeneration from MPS IH. In addition, ERT initiated during the asymptomatic period prevented the patient from developing somatic manifestations and enabled successful HSCT in this case.


Assuntos
Terapia de Reposição de Enzimas/métodos , Transplante de Células-Tronco Hematopoéticas/métodos , Mucopolissacaridose I/terapia , Feminino , Glicosaminoglicanos/metabolismo , Humanos , Lactente , Recém-Nascido , Japão , Doenças por Armazenamento dos Lisossomos/terapia , Mucopolissacaridose I/metabolismo , Qualidade de Vida , Irmãos , Resultado do Tratamento
10.
Mol Genet Metab Rep ; 14: 3-9, 2018 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-29124014

RESUMO

Pompe disease is an autosomal recessive disorder caused by acid α-glucosidase (GAA) deficiency, which results in the accumulation of glycogen in lysosomes in multiple tissues, including cardiac, skeletal, and smooth muscle cells. Thus far, 558 sequence variants of the GAA gene have been published in the Pompe Disease Mutation Database, and some mutations appear with considerable frequency in particular ethnic groups, such as Caucasians, Taiwanese, Chinese, and Koreans. However, the GAA mutation pattern in Japanese patients remains poorly understood. We analyzed the relationship between the genetic and clinical features of 38 mostly Japanese patients with Pompe disease from 35 unrelated families. We identified 28 different GAA gene mutations, including 7 novel mutations, by a GAA gene analysis. c.546G > T (22.9%) and c.1857C > G (14.3%) were the most common mutations and accounted for 37.1% of the total mutant alleles. In the six patients with infantile-onset Pompe disease (IOPD), c.1857C > G was also the most common mutation. In addition, there were 13 homozygotes (5 with the c.546G > T) among the 35 families, which is the highest frequency reported thus far. Regarding the initial symptoms, cardiomegaly was the most common (3/6 = 50%) in IOPD patients, while muscle weakness was observed the most frequently in patients with late-onset Pompe disease (LOPD) (15/30 = 50%). Notably, all IOPD patients who showed respiratory distress at the time of onset require respiratory assistance at present (4/4 = 100%). Regarding the presenting symptoms, cardiomegaly (6/6 = 100%) and hepatomegaly (4/6 = 66.7%) were more commonly seen in IOPD, and muscle weakness (24/29 = 82.7%) was observed more frequently in LOPD. Respiratory assistance is required at present in 33.3% of IOPD patients and 50% of LOPD patients, and 20% of IOPD patients and 29.6% of LOPD patients are wheelchair users. These individual clinical courses may be influenced by the timing of the diagnosis and treatment; for example, in 2007, an ERT orphan drug for treatment of Pompe disease, Alglucosidase alfa, was made available in Japan, and there were 5 (5/6 = 83.3%) wheelchair users diagnosed from 2008 to 2009 (cases 32-38) and 4 (4/27 = 14.8%) from 2010 to 2015 (cases 1-31). These findings underscore the importance of the early diagnosis and treatment.

11.
PLoS One ; 12(11): e0187810, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29121675

RESUMO

Steatosis has a low tolerance against ischemia-reperfusion injury (IRI). To prevent IRI in the steatotic liver, we attempted to elucidate the protective effect of astaxanthin (ASTX) in the steatotic liver model by giving mice a methionine and choline-deficient high fat (MCDHF) diet. Levels of lipid peroxidation and apoptosis, the expression of inflammatory cytokines and heme oxygenase (HO)-1, in the liver were assessed. Reactive oxygen species (ROS), inflammatory cytokines, apoptosis-related proteins and members of the signaling pathway were also examined in isolated Kupffer cells and/or hepatocytes from the steatotic liver. ASTX decreased serum ALT and AST levels, the amount of TUNEL, F4/80, or 4HNE-positive cells and the mRNA levels of inflammatory cytokines in MCDHF mice by IRI. Moreover, HO-1 and HIF-1α, phosphorylation of Akt and mTOR expressions were increased by ASTX. The inflammatory cytokines produced by Kupffer, which were subjected to hypoxia and reoxygenation (HR), were inhibited by ASTX. Expressions of Bcl-2, HO-1 and Nrf2 in hepatocytes by HR were increased, whereas Caspases activation, Bax and phosphorylation of ERK, MAPK, and JNK were suppressed by ASTX. Pretreatment with ASTX has a protective effect and is a safe therapeutic treatment for IRI, including for liver transplantation of the steatotic liver.


Assuntos
Citoproteção/efeitos dos fármacos , Fígado/efeitos dos fármacos , Hepatopatia Gordurosa não Alcoólica/complicações , Traumatismo por Reperfusão/complicações , Traumatismo por Reperfusão/prevenção & controle , Animais , Apoptose/efeitos dos fármacos , Hipóxia Celular/efeitos dos fármacos , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Heme Oxigenase-1/metabolismo , Hepatócitos/efeitos dos fármacos , Hepatócitos/patologia , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Células de Kupffer/efeitos dos fármacos , Células de Kupffer/metabolismo , Células de Kupffer/patologia , Fígado/metabolismo , Fígado/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Oxigênio/metabolismo , Fosforilação/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Traumatismo por Reperfusão/metabolismo , Traumatismo por Reperfusão/patologia , Transdução de Sinais/efeitos dos fármacos , Serina-Treonina Quinases TOR/metabolismo , Xantofilas/farmacologia , Proteína X Associada a bcl-2/metabolismo
12.
Nihon Rinsho ; 63(3): 403-7, 2005 Mar.
Artigo em Japonês | MEDLINE | ID: mdl-15773337

RESUMO

Present status of genetic medicine in Japan is reviewed. More than five hundred medical doctors have now been qualified as Japanese board of clinical genetics. Training courses for genetic counselors have started in several colleges. Thirty-six hospitals organized by University or National Centers have independent units of clinical genetics. Two major Japanese homepages concerning about clinical genetics are available. Ethical guidelines for gene testing and prenatal diagnosis are published by Japanese Society for Human Genetics and other Japanese medical societies. Infrastructure for clinical genetics are now rapidly organized in Japan, however lots of problems are still waiting to be solved.


Assuntos
Terapia Genética/normas , Humanos , Japão
14.
Mol Ther ; 13(3): 548-55, 2006 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-16316785

RESUMO

The therapeutic efficacy of neural stem cell transplantation for central nervous system (CNS) lesions in lysosomal storage disorders was explored using a murine model of mucopolysaccharidosis type VII (MPS VII). We used fetal neural stem cells derived from embryonic mouse striata and expanded in vitro by neurosphere formation as the source of graft materials. We transplanted neurospheres into the lateral ventricles of newborn MPS VII mice and found that donor cells migrated far beyond the site of injection within 24 h, and some of them could reach the olfactory bulb. A quantitative measurement indicated that the GUSB activity in the brain was 12.5 to 42.3% and 5.5 to 6.3% of normal activity at 24 h and 3 weeks after transplantation. In addition, histological analysis revealed a widespread decrease in lysosomal storage in the recipient's hippocampus, cortex, and ependyma. A functional assessment with novel-object recognition tests confirmed improvements in behavioral patterns. These results suggest that intracerebral transplantation of neural stem cells is feasible for treatment of CNS lesions associated with lysosomal storage disorders.


Assuntos
Terapia Genética , Glucuronidase/genética , Mucopolissacaridose VII/patologia , Mucopolissacaridose VII/terapia , Transplante de Células-Tronco , Telencéfalo/fisiopatologia , Animais , Animais Recém-Nascidos , Comportamento Animal/fisiologia , Encéfalo/enzimologia , Encéfalo/patologia , Células-Tronco Embrionárias/enzimologia , Células-Tronco Embrionárias/metabolismo , Células-Tronco Embrionárias/transplante , Glucuronidase/análise , Glucuronidase/metabolismo , Audição/genética , Lisossomos/enzimologia , Camundongos , Camundongos Endogâmicos C3H , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Mucopolissacaridose VII/fisiopatologia , Neurônios/enzimologia , Neurônios/metabolismo , Transporte Proteico/genética
15.
J Hepatol ; 38(6): 784-92, 2003 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-12763372

RESUMO

BACKGROUND/AIMS: When a loss of hepatic mass occurs, the expression of a large number of genes is either induced or altered, accompanying hepatocyte proliferation. In the present study, we made an in-house cDNA microarray containing 4608 elements (Liver chip), and analyzed extensively gene expression profiles of the regenerating liver after 70% partial hepatectomy (PHx) in rats. METHODS: RNAs were prepared from three rat livers at each time point (taken at 0, 6, 12, 18, 24, 48, 72 h, and 1 week after PHx). Using the liver chip, we performed large-scale analysis of gene expression during liver regeneration. Elements either up- or down-regulated more than twofold at one or more time points were selected. RESULTS: Among the 4608, 382 were identified. Using cluster analysis, we found great similarity between gene-expression profiles at 12 and 18 h after PHx as well as between 48 and 72 h after PHx. We also found that there are at least six distinct temporal patterns of gene expression in the regenerating rat liver after PHx. CONCLUSIONS: These results indicated that microarray analysis is a powerful approach for monitoring molecular events in the regenerating liver.


Assuntos
Perfilação da Expressão Gênica , Hepatectomia , Regeneração Hepática/genética , Animais , Análise por Conglomerados , Hepatectomia/métodos , Masculino , Análise de Sequência com Séries de Oligonucleotídeos , Período Pós-Operatório , RNA/metabolismo , Ratos , Ratos Sprague-Dawley , Fatores de Tempo
16.
Mol Ther ; 5(3): 262-8, 2002 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-11863415

RESUMO

The short duration of expression of the transgenes is a major barrier to the clinical application of adenovirus-mediated gene therapy for hepatic enzyme deficiencies. Previous reports show that Fas-mediated apoptosis has a pivotal role in the rapid elimination of adenovirus-infected hepatocytes. After considering this result and our recent observation that murine hepatocytes can be protected from Fas-mediated apoptosis by expressing cytokine response modifier A (CrmA) in vivo, we hypothesized that CrmA coexpression could also prevent adenovirus-infected hepatocytes from rapid elimination and that this would make prolonged transgene expression achievable in vivo. To examine this, mice with congenital deficiency of lysosomal beta-glucuronidase (GUSB) were infected with recombinant adenoviruses expressing both CrmA and GUSB, and the duration of transgene expression was evaluated. The serum GUSB activity in the mice injected with a recombinant adenovirus expressing GUSB only became undetectable 60 days after the injection, whereas higher than normal GUSB activity was observed for at least 120 days in mice injected with adenoviruses expressing both GUSB and CrmA. Furthermore, we showed that exogenous CrmA expression could prevent the adenovirus-infected hepatocytes from cell death induced by cytotoxic T lymphocytes in vitro. These observations indicate that transgene expression after administration of E1-deleted adenovirus is prolonged by coexpression of the antiapoptotic protein CrmA.


Assuntos
Adenoviridae , Regulação da Expressão Gênica , Técnicas de Transferência de Genes , Vetores Genéticos , Fígado/fisiologia , Serpinas/genética , Transgenes/genética , Proteínas Virais , Animais , Camundongos , Serpinas/biossíntese , Transgenes/fisiologia
17.
Mol Ther ; 8(5): 718-25, 2003 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-14599804

RESUMO

Neonatal gene transfer using adenovirus vectors expressing human beta-glucuronidase (AxCAhGUS) resulted in pathological improvement in multiple visceral organs of mice with mucopolysaccharidosis type VII (MPSVII). However, the therapeutic effect on skeletal deformities and growth retardation, the major clinical symptoms in MPSVII, was not fully investigated by biochemical and histopathological analyses. In this study, we injected AxCAhGUS into a murine model of MPSVII (B6/MPSVII) within 24 h of birth and evaluated the therapeutic effects on skeletal deformities and growth retardation. High levels of beta-glucuronidase (GUSB) activity (approximately threefold higher than normal GUSB activity) were observed in the articular cartilage of the mice 30 days after the treatment. Histopathological study in the knee joints showed elimination of vacuole cells in the articular cartilage and growth plate. Subchondral bone near the articular surface was almost normal in the treated MPSVII mice. Long-term observation (for 140 days after treatment) indicated that characteristic phenotypes such as flattened face, hunched stature, and shortening of bone length in the treated mice were almost normal. These results demonstrate that a single injection of adenovirus vector into neonatal MPSVII mice is sufficient for long-term normalization of skeletal deformities and effective in pathological correction of the articular cartilage and growth plate.


Assuntos
Adenoviridae/genética , Técnicas de Transferência de Genes , Mucopolissacaridose VII/terapia , Animais , Animais Recém-Nascidos , Doenças Ósseas/patologia , Doenças Ósseas/terapia , Cartilagem/metabolismo , Linhagem Celular , Condrócitos/metabolismo , DNA Viral/genética , Modelos Animais de Doenças , Endocitose , Vetores Genéticos , Glucuronidase/metabolismo , Humanos , Fígado/metabolismo , Camundongos , Fenótipo , Receptor IGF Tipo 2/metabolismo , Fatores de Tempo
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