ORCID Profile
0000-0001-8226-2618
Current Organisation
National Center For Child Health and Development
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Publisher: S. Karger AG
Date: 21-09-2016
DOI: 10.1159/000449222
Abstract: b i Background: /i /b i MECP2 /i duplication syndrome, which is caused by duplication of part of the Xq28 region containing the i MECP2 /i gene, causes intellectual disability and mild dysmorphic features in males. To date, precocious puberty has not been reported as a clinical feature of i MECP2 /i duplication syndrome. b i Methods: /i /b A 6-year-old male with severe intellectual disability was referred because of growth acceleration and precocious puberty. We checked his hormonal profile and conducted imaging studies and an array comparative genomic hybridization analysis. b i Results: /i /b His bone age (9 years and 6 months) was accelerated, and the basal level of testosterone was 8.99 ng/ml. In a luteinizing hormone (LH)-releasing hormone (LHRH) stimulation test, LH increased from 3.69 to 9.32 IU/l, and follicle-stimulating hormone increased from 0.65 to 0.90 IU/l. Chest and abdominal CTs and a brain MRI did not reveal any abnormalities. Treatment with an LHRH analogue effectively suppressed the level of testosterone to .03 ng/ml, consistent with the diagnosis of gonadotropin-dependent precocious puberty (GDPP). We identified a duplication of the Xq28 locus including i MECP2 /i in the patient. b i Conclusion: /i /b Precocious puberty is often a benign central process in girls, but it is rarely idiopathic in boys. The present case raises the possibility that GDPP is a novel clinical feature of i MECP2 /i duplication syndrome.
Publisher: Springer Science and Business Media LLC
Date: 07-04-2016
DOI: 10.1038/HGV.2016.3
Publisher: Wiley
Date: 04-07-2019
Abstract: Type A insulin resistance (IR) is a rare form of severe congenital IR that is frequently caused by heterozygous mutations in the insulin receptor (INSR) gene. Although Type A IR requires appropriate intervention from the early stages of diabetes, proper diagnosis of this disease is challenging, and accumulation of cases with detailed clinical profiles and genotypes is required. Herein we report on six peripubertal patients with clinically diagnosed Type A IR, including four patients with an identified INSR mutation. To clarify the clinical features of Type A IR due to INSR mutation, we validated the clinical characteristics of Type A IR patients with identified INSR mutations by comparing them with mutation-negative patients. Four heterozygous missense mutations within the β-subunit of INSR were detected: Gly1146Arg, Arg1158Trp, Arg1201Trp, and one novel Arg1201Pro mutation. There were no obvious differences in clinical phenotypes, except for normal lipid metabolism and autosomal dominant inheritance, between Type A IR due to INSR mutations and Type A IR due to other factors. However, our analysis revealed that the extent of growth retardation during the fetal period is correlated with the severity of insulin signaling impairment. The present study details the clinical features of four patients with genetically proven Type A IR. Further accumulation of genetically proven cases and long-term treatment prognoses following early diagnosis are required to further elucidate the dynamics of this disease.
Publisher: Elsevier BV
Date: 11-2019
DOI: 10.1016/J.PEDIATRNEUROL.2019.05.006
Abstract: Ataxia telangiectasia is an autosomal recessive disorder characterized by cerebellar ataxia, telangiectases, immune defects, and a predisposition to malignancy. Quality of life is severely impaired by neurological symptoms. However, curative options for the neurological symptoms are limited. Recent studies have demonstrated short-term improvement in neurological symptoms with betamethasone therapy. However, the long-term and adverse effects of betamethasone are unclear. The aim of this study was to evaluate the long-term effects, benefits, and adverse effects of low-dose betamethasone in ataxia telangiectasia. Six patients with ataxia telangiectasia received betamethasone at 0.02 mg/kg/day for two years. After cessation of betamethasone, the patients were observed for two additional years. Neurological assessments were performed, and adverse effects were monitored every three months throughout the four-year study period. Transient improvement of neurological symptom was observed in five of the six patients. However, after two years betamethasone treatment, only one of the six patients showed a slight improvement in the neurological score, one patient showed no change, and the neurological scores of the remaining four patients deteriorated. After the cessation of betamethasone treatment, neurological symptoms worsened in all patients. As an adverse effect of betamethasone, transient adrenal dysfunction was observed in all cases. Although these findings are in agreement with previous studies suggesting that short-term betamethasone treatment transiently benefits patients with ataxia telangiectasia, the long-term benefits and risks should be carefully considered.
Publisher: Springer Science and Business Media LLC
Date: 05-09-2018
DOI: 10.1038/S41598-018-31376-8
Abstract: Peptidyl arginine deiminases (PADIs) are enzymes that change the charge of proteins through citrullination. We recently found Padi2 was expressed exclusively in fetal Sertoli cells. In this study, we analyzed the transcriptional regulation of Padi2 and the role of PADI2 in testicular development. We showed SOX9 positively regulated Padi2 transcription and FOXL2 antagonized it in TM3 cells, a model of Sertoli cells. The responsive region to SOX9 and FOXL2 was identified within the Padi2 sequence by reporter assay. In fetal testes from Sox9 knockout (AMH-Cre: Sox9 flox/flox ) mice, Padi2 expression was greatly reduced, indicating SOX9 regulates Padi2 in vivo . In vitro analysis using siRNA suggested PADI2 modified transcriptional regulation by SOX9. However, Padi2 −/− XY mice were fertile and showed no apparent reproductive anomalies. Although, PADI2 is known as an epigenetic transcriptional regulator through H3 citrullination, no significant difference in H3 citrullination between wildtype and Padi2 −/− XY gonads was observed. These results suggest Padi2 is a novel gene involved in testis development that is specifically expressed in Sertoli cells through the regulation by SOX9 and FOXL2 and PADI2 supports regulation of target genes by SOX9. Analysis of the Padi2 −/− XY phenotype suggested a redundant factor compensated for PADI2 function in testicular development.
Publisher: The Endocrine Society
Date: 08-09-2022
Abstract: There are limited reports on the detailed examination of steroid profiles for setting algorithms for 21-hydroxylase deficiency (21OHD) screening by liquid chromatography-tandem mass spectrometry (LC-MS/MS). We aimed to define an algorithm for newborn screening of 21OHD by LC-MS/MS, measuring a total of 2077 dried blood spot s les in Tokyo. Five steroids (17α-hydroxyprogesterone [17αOHP], 21-deoxycortisol [21DOF], 11-deoxycortisol [11DOF], androstenedione [4AD], and cortisol [F]) were included in the panel of LC-MS/MS. S les from 2 cohorts were assayed: Cohort A, 63 "screening positive" neonates who were referred to an endocrinologist (n = 26 with 21OHD n = 37 false-positive obtained from 2015 to 2020) and Cohort B, s les (n = 2014) with 17αOHP values in the 97th percentile or above, in the first-tier test with 17αOHP ELISA from 2020 to 2021. Analysis of Cohort A revealed that the 3 indexes 21DOF, 11DOF/17αOHP, and (4AD + 17αOHP)/F had higher area under the curve (AUC) values (0.999, 0.997, 0.989, respectively), while the 17αOHP AUC was lower (0.970). Accordingly, in addition to 17αOHP, the 3 markers were included for defining the screening algorithm. The assay of Cohort B revealed that the new algorithm gave 92% of predicted positive predictive value without false-negative cases. We also determined the reference values for the 5 steroids at 4 to 7 days after birth, according to sex and gestational age (GA), revealing extremely low levels of 21DOF at any GA irrespective of sex differences. Our study demonstrated the high relevance of 21DOF, (4AD + 17αOHP)/F, and 11DOF/17αOHP, rather than 17αOHP, for 21OHD screening.
Publisher: The Endocrine Society
Date: 06-10-2023
Publisher: Springer Science and Business Media LLC
Date: 24-04-2018
DOI: 10.1007/S12020-018-1595-3
Abstract: Hematopoietic stem cell transplantation (HSCT) is a curative treatment for life-threatening malignancies and related diseases. Recently, the long-term prognosis of HSCT during childhood has greatly improved however, the late adverse effects of HSCT have been found to cause substantial morbidity among long-term survivors. Although metabolic complications, such as diabetes mellitus (DM) and hyperlipidemia (HL), are the major late effects of pediatric HSCT, the clinical details are not clarified sufficiently. From 1983 to 2013, 75 participants underwent HSCT in our institute because of malignant or other related diseases. We retrospectively evaluated metabolic complications of eligible 22 participants (14 men and 8 women), and their clinical backgrounds. Among 22 participants, 4 and 9 participants developed DM and HL after HSCT, respectively, and all participants with DM developed HL. None of the participants with DM were obese, and all had substantial insulin resistance. Total body irradiation (TBI) was performed in 10 participants, including 4 participants with DM and 5 participants with HL, revealing that TBI is an independent risk factor for DM. The age at TBI for participants with DM was significantly lower than that for participants without DM (p = 0.01), and all participants with DM received TBI before the age of 6. Our data suggested that TBI was a risk factor for DM after HSCT, and TBI before the age of six increased the possibility of DM without obesity.
Publisher: Japanese Society for Pediatric Endocrinology
Date: 2019
DOI: 10.1297/CPE.28.105
Publisher: Hindawi Limited
Date: 09-02-2017
DOI: 10.1111/PEDI.12508
Abstract: Defects of the insulin receptor gene ( INSR ) cause wide spectra of congenital insulin resistance. Monoallelic defects result in milder insulin-resistant diabetes mellitus with acanthosis nigricans (IRAN, type A). Whereas, leprechaunism (Donahue syndrome), the most severe condition with lethality during the infantile period is caused by biallelic defects of INSR . We detected 2 missense mutations in 2 cases of leprechaunism and IRAN, type A, and reduced mRNA expression in the leprechaunism case. We performed an in vitro analysis to confirm that the 2 missense mutations are causative. The heterozygote mutations c.3436G>A (p.Gly1146Arg) and c.294C>A (p.Ser98Arg) were identified in a male patient with IRAN, type A and a female patient with leprechaunism, respectively. Gly1146Arg was previously reported in a diabetic case without precise functional analyses, and Ser98Arg is a novel mutation. Gly1146 and Ser98 are located on the tyrosine kinase domain and ligand-binding domain of INSR, respectively, and in vitro analyses (assay for insulin binding and phosphorylation) revealed that each mutation disrupted protein functions and properties. In the leprechaunism case, mutations in INSR other than Ser98Arg were not identified, and qRT-PCR analysis revealed that mRNA expression of INSR in lymphocytes was reduced in the leprechaunism case. Our study indicates that the 2 missense mutations of INSR , Gly1146Arg, and Ser98Arg, are responsible for insulin resistance, and, suggests that mutations not contained within INSR , but leading to decreased INSR expression should be considered for the patients who show insulin resistance without any mutations in the coding sequence of INSR.
Publisher: Springer Science and Business Media LLC
Date: 12-2015
Publisher: Wiley
Date: 20-10-2020
DOI: 10.1111/CEN.14347
Publisher: Cold Spring Harbor Laboratory
Date: 25-05-2018
DOI: 10.1101/331090
Abstract: The nuclear receptor NR5A1 (also known as Ad4BP, or SF1) is essential for the initial steps of mammalian gonadal development. The Nr5a1 gene is equally expressed in XX and XY gonadal primordia, but after sex determination, is up-regulated in XY and down-regulated in XX gonads. We recently reported a case of 46, XX disorder of sex development (DSD) in which ectopically expressed NR5A1 in XX gonads led to an ovo-testicular phenotype, suggesting that excess NR5A1 can direct the development of immature XX gonads towards testicular formation. However, a direct causal relationship has not been demonstrated in an animal model. Here, using a Wt1-BAC (bacterial artificial chromosome) transgene system, we generated two lines of mice overexpressing Nr5a1 in the fetal gonads at different levels. One of these lines (Tg-S), highly expressing Nr5a1, revealed that enforced Nr5a1 expression alone is insufficient to switch the fate of the 46,XX gonads toward testicular formation in mice. In the other line (Tg-A) expressing Nr5a1 at lower level, ovarian development was compromised, with multi-oocyte follicles, reduced number of matured follicles, and impaired expression of Wnt4, resulting in late onset infertility at 20 weeks after birth. The phenotype was similar to that of genetically modified mice with impaired Notch signaling. Indeed, the expression level of Notch2 and 3 was significantly reduced in Tg-A mice, and the ovarian phenotype in Tg-A mice was almost completely rescued by in utero treatment with a Notch2 agonist HMN2-29. We conclude that suppression of Nr5a1 during the fetal period optimizes ovarian development by fine tuning of Notch signaling levels. Sexual development is a process of differentiation from undifferentiated bipotential gonads, and insight into sexual differentiation will bring important new knowledge to our understanding of organogenesis. The nuclear receptor NR5A1 which is essential for mammalian gonadal development, is equally expressed in both gonadal primordia, but after sex determination, is up-regulated in XY and down-regulated in XX gonads. We have recently demonstrated that this down-regulation is mediated by ovarian transcription factor, Forkhead box L2 (FOXL2). This finding raised two key questions, whether Nr5a1 can function as a male sex-determining factor, and whether the repression is essential for appropriate ovarian development. By generating two lines Tg mice in XX gonads with different enforced expression levels of Nr5a1, our present study revealed that alterations in Nr5a1 dosage, either reduced or excessive, result in pathological effects in ovarian development and female fertility, indicating that the precise control of Nr5a1 at the transcriptional level is essential for optimal ovarian development. We envisage that the improved understanding of how this pathway regulates ovarian development and female fertility would aid the development of artificial somatic ovarian cells, which in turn may provide a valuable treatment option in reproductive medicine. BAC bacterial artificial chromosome dpc days post coitum FOXL2 Forkhead box L2 HSD hydroxysteroid dehydrogenase IF Immunofluorescence MOFs multiple oocyte follicles PFA paraformaldehyde qRT-PCR Quantitative real-time PCR Rps29 Ribosomal protein S29 SRY sex-determining region Y
Publisher: Japan Endocrine Society
Date: 2016
Publisher: The Company of Biologists
Date: 2019
DOI: 10.1242/JCS.223768
Abstract: The nuclear receptor NR5A1 is equally expressed and required for development of the gonadal primordia of both sexes, but after sex determination, it is up-regulated in XY testes and down-regulated in XX ovaries. We have recently demonstrated that this down-regulation is mediated by Forkhead box L2 (FOXL2) and hypothesized that adequate suppression of Nr5a1 may be essential for normal ovarian development. Further, analysis of human patients with Disorders/Differences of Sex Development suggests that overexpression of NR5A1 can result in XX (ovo)testicular development. Here, we tested the role of Nr5a1 by overexpression in fetal gonads using a Wt1-BAC (bacterial artificial chromosome) transgene system. Enforced Nr5a1 expression compromised ovarian development in 46,XX mice, resulting in late onset infertility, but did not induce (ovo)testis differentiation. The phenotype was similar to that of XX mice lacking Notch signaling. The expression level of Notch2 was significantly reduced in Nr5a1 transgenic mice, and the ovarian phenotype was almost completely rescued by in utero treatment with a NOTCH2 agonist. We conclude that suppression of Nr5a1 during the fetal period optimizes ovarian development by fine-tuning of Notch signaling.
Publisher: Oxford University Press (OUP)
Date: 03-02-2022
DOI: 10.1093/HMG/DDAC023
Abstract: The genetic regulation of ovarian development remains largely unclear. Indeed, in most cases of impaired ovarian development—such as 46,XX disorders of sex development (DSD) without SRY, and premature ovarian insufficiency (POI)—the genetic causes have not been identified, and the vast majority of disease-associated sequence variants could lie within non-coding regulatory sequences. In this study, we aimed to identify enhancers of five ovarian genes known to play key roles in early ovarian development, basing our analysis on the expression of enhancer derived transcripts (eRNAs), which are considered to characterize active enhancers. Temporal expression profile changes in mouse WT1-positive ovarian cells were obtained from cap analysis of gene expression at E13.5, E16.5 and P0. We compared the chronological expression profiles of ovarian-specific eRNA with expression profiles for each of the ovarian-specific genes, yielding two candidate sequences for enhancers of Wnt4 and Rspo1. Both sequences are conserved between mouse and human, and we confirmed their enhancer activities using transient expression assays in murine granulosa cells. Furthermore, by sequencing the region in patients with impaired ovarian development in 24 patients, such as POI, gonadal dysgenesis and 46,XX DSD, we identified rare single nucleotide variants in both sequences. Our results demonstrate that combined analysis of the temporal expression profiles of eRNA and mRNA of target genes presents a powerful tool for locating cis-element enhancers, and a means of identifying disease-associated sequence variants that lie within non-coding regulatory sequences, thus advancing an important unmet need in forward human genetics.
Publisher: Japanese Society for Pediatric Endocrinology
Date: 2018
DOI: 10.1297/CPE.27.31
Location: No location found
No related grants have been discovered for Atsumi Tsuji-Hosokawa.