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Article: Placental Mesenchymal Dysplasia and Beckwith-Wiedemann Syndrome.

Soejima, Hidenobu / Hara, Satoshi / Ohba, Takashi / Higashimoto, Ken

2022 Volume 14, Issue 22

Abstract: Placental mesenchymal dysplasia (PMD) is characterized by placentomegaly, aneurysmally dilated chorionic plate vessels, thrombosis of the dilated vessels, and large grapelike vesicles, and is often mistaken for partial or complete hydatidiform mole with ... ...

Abstract	Placental mesenchymal dysplasia (PMD) is characterized by placentomegaly, aneurysmally dilated chorionic plate vessels, thrombosis of the dilated vessels, and large grapelike vesicles, and is often mistaken for partial or complete hydatidiform mole with a coexisting normal fetus. Androgenetic/biparental mosaicism (ABM) has been found in many PMD cases. Beckwith-Wiedemann syndrome (BWS) is an imprinting disorder with complex and diverse phenotypes and an increased risk of developing embryonal tumors. There are five major causative alterations: loss of methylation of imprinting control region 2 (
Language	English
Publishing date	2022-11-12
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2527080-1
ISSN	2072-6694
ISSN	2072-6694
DOI	10.3390/cancers14225563
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Article ; Online: DNA Methylation Analysis Using Bisulfite Pyrosequencing.

Higashimoto, Ken / Hara, Satoshi / Soejima, Hidenobu

Methods in molecular biology (Clifton, N.J.)

2022 Volume 2577, Page(s) 3–20

Abstract: Pyrosequencing is a DNA sequencing-by-synthesis technique that can quantitatively detect single-nucleotide polymorphisms (SNPs). With pyrosequencing, the level of DNA methylation can be calculated according to the ratio of artificial cytosine/thymine ... ...

Abstract	Pyrosequencing is a DNA sequencing-by-synthesis technique that can quantitatively detect single-nucleotide polymorphisms (SNPs). With pyrosequencing, the level of DNA methylation can be calculated according to the ratio of artificial cytosine/thymine SNPs produced by bisulfite conversion at each CpG site. This analysis method provides a reproducible and accurate measurement of methylation levels at CpG sites near sequencing primers with high quantitative resolution. DNA methylation plays an important role in mammalian development and cellular physiology; alterations in DNA methylation patterns have been implicated in several common diseases as well as cancers and imprinting disorders. Evaluating DNA methylation levels via pyrosequencing is useful for identifying biomarkers that could help with the diagnosis, prognosis, treatment selection, and onset risk assessment for several diseases. We describe the principles of pyrosequencing and detail a bisulfite pyrosequencing protocol based on our experience and the PyroMark Q24 User Manual.
MeSH term(s)	Animals ; CpG Islands ; Cytosine ; DNA Methylation/genetics ; DNA Primers/genetics ; High-Throughput Nucleotide Sequencing/methods ; Mammals/genetics ; Polymorphism, Single Nucleotide/genetics ; Sequence Analysis, DNA/methods ; Sulfites ; Thymine
Chemical Substances	DNA Primers ; Sulfites ; Cytosine (8J337D1HZY) ; hydrogen sulfite (OJ9787WBLU) ; Thymine (QR26YLT7LT)
Language	English
Publishing date	2022-09-29
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ISSN	1940-6029
ISSN (online)	1940-6029
DOI	10.1007/978-1-0716-2724-2_1
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Article ; Online: Whole-exome sequencing reveals causative genetic variants for several overgrowth syndromes in molecularly negative Beckwith-Wiedemann spectrum.

Higashimoto, Ken / Sun, Feifei / Imagawa, Eri / Saida, Ken / Miyake, Noriko / Hara, Satoshi / Yatsuki, Hitomi / Kubiura-Ichimaru, Musashi / Fujita, Atsushi / Mizuguchi, Takeshi / Matsumoto, Naomichi / Soejima, Hidenobu

Journal of medical genetics

2024

Abstract: ... ...

Abstract	Background
Language	English
Publishing date	2024-01-16
Publishing country	England
Document type	Journal Article
ZDB-ID	220881-7
ISSN	1468-6244 ; 0022-2593
ISSN (online)	1468-6244
ISSN	0022-2593
DOI	10.1136/jmg-2023-109621
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Zs.A 177: Show issues

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Article ; Online: Possible regulation of ganglioside GD3 synthase gene expression with DNA methylation in human glioma cells.

Yamamoto, Yurie / Higashimoto, Ken / Ohkawa, Yuki / Soejima, Hidenobu / Kaneko, Kei / Ohmi, Yuhsuke / Furukawa, Keiko / Furukawa, Koichi

Glycoconjugate journal

2023 Volume 40, Issue 3, Page(s) 323–332

Abstract: Gangliosides are expressed in nervous systems and some neuroectoderm-derived tumors at high levels and play pivotal roles. However, mechanisms for the regulation of glycosyltransferase genes responsible for the ganglioside synthesis are not well ... ...

Abstract	Gangliosides are expressed in nervous systems and some neuroectoderm-derived tumors at high levels and play pivotal roles. However, mechanisms for the regulation of glycosyltransferase genes responsible for the ganglioside synthesis are not well understood. In this study, we analyzed DNA methylation patterns of promoter regions of GD3 synthase (ST8SIA1) as well as mRNA levels and ganglioside expression using human glioma cell lines. Among 5 cell lines examined, 4 lines showed changes in the expression levels of related genes after treatment with 5-aza-dC. LN319 showed up-regulation of St8sia1 and increased b-series gangliosides after 5-aza-dC treatment, and an astrocytoma cell line, AS showed high expression of ST8SIA1 and b-series gangliosides persistently before and after 5-Aza-2'-deoxycytidine treatment. Using these 2 cell lines, DNA methylation patterns of the promoter regions of the gene were analyzed by bisulfite-sequencing. Consequently, 2 regions that were methylated before 5-Aza-2'-deoxycytidine treatment were demethylated in LN319 after the treatment, while those regions were persistently demethylated in AS. These 2 regions corresponded with sites defined as promoter regions by Luciferase assay. Taken together, it was suggested that ST8SIA1 gene is regulated by DNA methylation at the promoter regions, leading to the regulation of tumor phenotypes.
MeSH term(s)	Humans ; Azacitidine/pharmacology ; Azacitidine/metabolism ; Cell Line, Tumor ; Decitabine/pharmacology ; Decitabine/metabolism ; DNA Methylation/genetics ; Gangliosides/genetics ; Gangliosides/metabolism ; Gene Expression ; Gene Expression Regulation, Neoplastic ; Glioma/genetics ; Glioma/metabolism ; Glioma/pathology ; Promoter Regions, Genetic/genetics
Chemical Substances	Azacitidine (M801H13NRU) ; Decitabine (776B62CQ27) ; ganglioside, GD3 (62010-37-1) ; Gangliosides ; alpha-N-acetylneuraminate alpha-2,8-sialyltransferase (EC 2.4.99.8)
Language	English
Publishing date	2023-03-10
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	283770-5
ISSN	1573-4986 ; 0282-0080
ISSN (online)	1573-4986
ISSN	0282-0080
DOI	10.1007/s10719-023-10108-9
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Zs.A 2171: Show issues

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Article ; Online: Phenotypically concordant but epigenetically discordant monozygotic dichorionic diamniotic twins with Beckwith-Wiedemann syndrome.

Sun, Feifei / Hara, Satoshi / Tomita, Chiyoko / Tanoue, Yuka / Yatsuki, Hitomi / Higashimoto, Ken / Soejima, Hidenobu

American journal of medical genetics. Part A

2021 Volume 185, Issue 10, Page(s) 3062–3067

Abstract: Beckwith-Wiedemann syndrome (BWS) is an imprinting disorder caused by (epi)genetic alterations. The incidence of monozygotic (MZ) twins in BWS is higher than in the general population. Most MZ twins with BWS are female and have phenotypical discordance: ... ...

Abstract	Beckwith-Wiedemann syndrome (BWS) is an imprinting disorder caused by (epi)genetic alterations. The incidence of monozygotic (MZ) twins in BWS is higher than in the general population. Most MZ twins with BWS are female and have phenotypical discordance: one twin is clinically diagnosed with BWS, while the other shows a mild or normal phenotype. The most frequent (epi)genetic alteration in MZ twins is loss of methylation of imprinting control region 2 (ICR2-LOM) at 11p15.5. Intriguingly, ICR2-LOM is usually found in the peripheral blood leukocytes (PBL) of both twins, even if they are clinically discordant. Here, we present a rare pair of MZ dichorionic diamniotic female twins with BWS and concordant phenotypes (a Beckwith-Wiedemann spectrum score of 5 in each twin). Molecular analysis of genomic DNA from PBL revealed ICR2-LOM in one twin but not the other. Our analyses suggest that ICR2-LOM occurred between days 1 and 3 after fertilization, followed by twinning. We speculate that during embryogenesis, ICR2-LOM cells were distributed to the hematopoietic stem cells in different ratios in the two fetuses, and also to commonly affected tissues, such as the tongue, in similar ratios, although we were unable to analyze any tissues other than PBL.
MeSH term(s)	Beckwith-Wiedemann Syndrome/genetics ; Beckwith-Wiedemann Syndrome/pathology ; DNA Methylation/genetics ; Diseases in Twins/genetics ; Diseases in Twins/pathology ; Epigenomics ; Female ; Genomic Imprinting/genetics ; Humans ; Male ; Phenotype ; Twins, Monozygotic/genetics
Language	English
Publishing date	2021-05-26
Publishing country	United States
Document type	Case Reports ; Research Support, Non-U.S. Gov't
ZDB-ID	2108614-X
ISSN	1552-4833 ; 0148-7299 ; 1552-4825
ISSN (online)	1552-4833
ISSN	0148-7299 ; 1552-4825
DOI	10.1002/ajmg.a.62364
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Zs.A 1376/A: Show issues

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Article ; Online: Donor cord blood aging accelerates in recipients after transplantation.

Onizuka, Makoto / Imanishi, Tadashi / Harada, Kaito / Aoyama, Yasuyuki / Amaki, Jun / Toyosaki, Masako / Machida, Shinichiro / Kikkawa, Eri / Yamada, Sanetoshi / Nakabayashi, Kazuhiko / Hata, Kenichiro / Higashimoto, Ken / Soejima, Hidenobu / Ando, Kiyoshi

Scientific reports

2023 Volume 13, Issue 1, Page(s) 2603

Abstract: Cord blood stem cell transplantation is an important alternative for patients needing hematopoietic stem cell transplantation. However, it is unclear how cord blood cells, which are 0 years old, age in the recipient's body after allogeneic ... ...

Abstract	Cord blood stem cell transplantation is an important alternative for patients needing hematopoietic stem cell transplantation. However, it is unclear how cord blood cells, which are 0 years old, age in the recipient's body after allogeneic transplantation. We performed DNA methylation (DNAm) age analysis to measure the age of cells using post-transplant peripheral blood in 50 cases of cord blood transplantation. The median chronological age (the time elapsed from the date of the cord blood transplant to the day the sample was taken for DNAm analysis) of donor cells was 4.0 years (0.2-15.0 years), while the median DNAm age was 10.0 years (1.3-30.3 years), and the ratio of DNAm age to chronological age (AgeAccel) was 2.7 (1.2-8.2). When comparing the mean values of AgeAccel in cord blood transplant cases and controls, the values were significantly higher in cord blood transplant cases. The characteristics of patients and transplant procedures were not associated with AgeAccel in this analysis, nor were they associated with the development of graft-versus-host disease. However, this analysis revealed that transplanting 0-year-old cord blood into a recipient resulted in cells aging more than twice as quickly as the elapsed time. The results shed light on the importance of the mismatch between cord blood stem cells and donor environmental factors in stem cell aging.
MeSH term(s)	Humans ; Infant, Newborn ; Child ; Fetal Blood ; Hematopoietic Stem Cell Transplantation/adverse effects ; Hematopoietic Stem Cell Transplantation/methods ; Transplantation, Homologous ; Graft vs Host Disease ; Blood Donors ; Cellular Senescence ; Cord Blood Stem Cell Transplantation/adverse effects
Language	English
Publishing date	2023-02-14
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2615211-3
ISSN	2045-2322 ; 2045-2322
ISSN (online)	2045-2322
ISSN	2045-2322
DOI	10.1038/s41598-023-29912-2
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Article ; Online: Clinical manifestations of placental mesenchymal dysplasia in Japan: A multicenter case series.

Kodera, Chisato / Aoki, Saori / Ohba, Takashi / Higashimoto, Ken / Mikami, Yoshiki / Fukunaga, Masaharu / Soejima, Hidenobu / Katabuchi, Hidetaka

The journal of obstetrics and gynaecology research

2021 Volume 47, Issue 3, Page(s) 1118–1125

Abstract: Aim: This study aimed to evaluate the clinical features and pregnancy outcomes of placental mesenchymal dysplasia (PMD) in Japan.: Methods: We requested detailed clinical information and placental tissue of PMD cases in 2000-2018 from Japanese ... ...

Abstract	Aim: This study aimed to evaluate the clinical features and pregnancy outcomes of placental mesenchymal dysplasia (PMD) in Japan. Methods: We requested detailed clinical information and placental tissue of PMD cases in 2000-2018 from Japanese facilities with departments of obstetrics and gynecology and analyzed the pregnancy course and neonatal outcomes. Results: We collected 49 cases of PMD. Of 18 patients with measured maternal serum alpha-fetoprotein (MSAFP) levels, 15 (83.3%) had elevated levels. Maternal serum human chorionic gonadotropin (MShCG) levels were transiently elevated in five (17.8%) of 28 patients. Forty-seven patients continued their pregnancies. All pregnancies were singleton and 40 (85.1%) were associated with adverse events including fetal growth restriction (FGR), threatened premature delivery, fetal demise, and hypertensive disorder of pregnancy in 34 (72.3%), 14 (29.8%), eight (17.0%), and six (12.8%) patients, respectively. Of 47 infants, there were eight stillbirths. There were 40 (85.1%) female infants, and eight (17.0%) had Beckwith-Wiedemann syndrome. Of 39 live births, 23 (59.0%) were associated with premature induction of labor or cesarean section for obstetric indications related to FGR. Eighteen (46.2%) neonates had complications. PMD-affected placentas were pathologically heterogeneous in both grossly PMD-affected and non-affected areas. Conclusions: Our study included the largest number of PMD cases with detailed clinical information. PMD is a high-risk condition for both the mother and the child. Elevated MSAFP levels with normal MShCG levels indicate PMD. Conventional perinatal management of FGR in Japan might be effective in reducing the fetal mortality rate.
MeSH term(s)	Cesarean Section ; Child ; Female ; Humans ; Infant, Newborn ; Japan/epidemiology ; Placenta ; Placenta Diseases ; Pregnancy ; Pregnancy Outcome
Language	English
Publishing date	2021-01-18
Publishing country	Australia
Document type	Journal Article ; Multicenter Study
ZDB-ID	1327307-3
ISSN	1447-0756 ; 1341-8076
ISSN (online)	1447-0756
ISSN	1341-8076
DOI	10.1111/jog.14647
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Zs.A 1810: Show issues

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Article ; Online: Epigenetic and genetic alterations of the imprinting disorder Beckwith-Wiedemann syndrome and related disorders.

Soejima, Hidenobu / Higashimoto, Ken

Journal of human genetics

2013 Volume 58, Issue 7, Page(s) 402–409

Abstract: Genomic imprinting is an epigenetic phenomenon that leads to parent-specific differential expression of a subset of genes. Most imprinted genes form clusters, or imprinting domains, and are regulated by imprinting control regions. As imprinted genes have ...

Abstract	Genomic imprinting is an epigenetic phenomenon that leads to parent-specific differential expression of a subset of genes. Most imprinted genes form clusters, or imprinting domains, and are regulated by imprinting control regions. As imprinted genes have an important role in growth and development, aberrant expression of imprinted genes due to genetic or epigenetic abnormalities is involved in the pathogenesis of human disorders, or imprinting disorders. Beckwith-Wiedemann syndrome (BWS) is a representative imprinting disorder characterized by macrosomia, macroglossia and abdominal wall defects, and exhibits a predisposition to tumorigenesis. The relevant imprinted chromosomal region in BWS is 11p15.5, which consists of two imprinting domains, IGF2/H19 and CDKN1C/KCNQ1OT1. BWS has five known causative epigenetic and genetic alterations: loss of methylation (LOM) at KvDMR1, gain of methylation (GOM) at H19DMR, paternal uniparental disomy, CDKN1C mutations and chromosomal rearrangements. Opposite methylation defects, GOM and LOM, at H19DMR are known to cause clinically opposite disorders: BWS and Silver-Russell syndrome, respectively. Interestingly, a recent study discovered that loss of function or gain of function of CDKN1C also causes clinically opposite disorders, BWS and IMAGe (intrauterine growth restriction, metaphyseal dysplasia, adrenal hypoplasia congenita, and genital anomalies) syndrome, respectively. Furthermore, several clinical studies have suggested a relationship between assisted reproductive technology (ART) and the risk of imprinting disorders, along with the existence of trans-acting factors that regulate multiple imprinted differentially methylated regions. In this review, we describe the latest knowledge surrounding the imprinting mechanism of 11p15.5, in addition to epigenetic and genetic etiologies of BWS, associated childhood tumors, the effects of ART and multilocus hypomethylation disorders.
MeSH term(s)	Beckwith-Wiedemann Syndrome/genetics ; Chromosomes, Human, Pair 11/genetics ; Cyclin-Dependent Kinase Inhibitor p57/genetics ; Cyclin-Dependent Kinase Inhibitor p57/metabolism ; DNA Methylation ; Gene Rearrangement ; Genetic Loci ; Genetic Predisposition to Disease ; Genomic Imprinting ; Humans ; Mutation ; Uniparental Disomy/genetics
Chemical Substances	CDKN1C protein, human ; Cyclin-Dependent Kinase Inhibitor p57
Language	English
Publishing date	2013-07
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	1425192-9
ISSN	1435-232X ; 1434-5161
ISSN (online)	1435-232X
ISSN	1434-5161
DOI	10.1038/jhg.2013.51
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Zs.A 201: Show issues

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Article ; Online: Hypomethylation of a centromeric block of ICR1 is sufficient to cause Silver-Russell syndrome.

Higashimoto, Ken / Watanabe, Hijiri / Tanoue, Yuka / Tonoki, Hidefumi / Tokutomi, Tomoharu / Hara, Satoshi / Yatsuki, Hitomi / Soejima, Hidenobu

Journal of medical genetics

2020 Volume 58, Issue 6, Page(s) 422–425

Abstract: Silver-Russell syndrome (SRS) is a representative imprinting disorder. A major cause is the loss of methylation (LOM) of imprinting control region 1 (ICR1) within ... ...

Abstract	Silver-Russell syndrome (SRS) is a representative imprinting disorder. A major cause is the loss of methylation (LOM) of imprinting control region 1 (ICR1) within the
MeSH term(s)	Catalytic Domain ; Centromere/metabolism ; Child ; Child, Preschool ; DNA Methylation ; Female ; Humans ; Insulin-Like Growth Factor II/genetics ; Male ; Promoter Regions, Genetic ; Regulatory Sequences, Nucleic Acid ; Silver-Russell Syndrome/genetics ; Telomere/metabolism
Chemical Substances	IGF2 protein, human ; Insulin-Like Growth Factor II (67763-97-7)
Language	English
Publishing date	2020-05-23
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	220881-7
ISSN	1468-6244 ; 0022-2593
ISSN (online)	1468-6244
ISSN	0022-2593
DOI	10.1136/jmedgenet-2020-106907
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Article ; Online: Hepatoblastoma in an extremely low birth-weight infant with Beckwith-Wiedemann syndrome.

Kawasaki, Yukako / Makimoto, Masami / Samejima, Azusa / Yoneda, Noriko / Higashimoto, Ken / Soejima, Hidenobu / Yoshida, Taketoshi

Pediatrics and neonatology

2017 Volume 59, Issue 5, Page(s) 523–524

Language	English
Publishing date	2017-11-21
Publishing country	Singapore
Document type	Journal Article
ZDB-ID	2441816-X
ISSN	2212-1692 ; 1875-9572
ISSN (online)	2212-1692
ISSN	1875-9572
DOI	10.1016/j.pedneo.2017.11.012
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