研究者詳細 - 荻　朋男

論文 - 荻　朋男

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Ceramide Analysis in Combination With Genetic Testing May Provide a Precise Diagnosis for Self-Healing Collodion Babies 査読有り国際誌

Takeichi Takuya, Ohno Yusuke, Tanahashi Kana, Ito Yasutoshi, Shiraishi Ken, Utsunomiya Ryo, Yoshida Satoshi, Ikeda Kenta, Nomura Hayato, Morizane Shin, Sayama Koji, Ogi Tomoo, Muro Yoshinao, Kihara Akio, Akiyama Masashi

JOURNAL OF LIPID RESEARCH 63 巻 ( 12 ) 頁： 100308 - 100308 2022年12月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Journal of Lipid Research

Self-healing collodion baby (SHCB), also called “self-improving collodion baby”, is a rare mild variant of autosomal recessive congenital ichthyosis and is defined as a collodion baby who shows the nearly complete resolution of scaling within the first 3 months to 1 year of life. However, during the neonatal period, it is not easy to distinguish SHCB from other inflammatory forms of autosomal recessive congenital ichthyosis, such as congenital ichthyosiform erythroderma. Here, we report a case study of two Japanese SHCB patients with compound heterozygous mutations, c.235G>T (p.(Glu79*))/ c.1189C>T (p.(Arg397Cys)) and c.1295A>G (p.(Tyr432-Cys))/ c.1138delG (p.(Asp380Thrfs*3)), in CYP4F22, which encodes cytochrome P450, family 4, subfamily F, polypeptide 22 (CYP4F22). Immunohistochemically, inflammation with the strong expression of IL-17C, IL-36γ, and TNF-α was seen in the skin at birth. CYP4F22 is an ultra-long-chain FA ω-hydroxylase responsible for ω-O-acylceramide (acylceramide) production. Among the epidermal ceramides, acylceramide is a key lipid in maintaining the epidermal permeability barrier function. We found that the levels of ceramides with ω-hydroxy FAs including acylceramides and the levels of protein-bound ceramides were much lower in stratum corneum samples obtained by tape stripping from SHCB patients than in those from their unaffected parents and individuals without SHCB. Additionally, our cell-based enzyme assay revealed that two mutants, p.(Glu79*) and p.(Arg397Cys), had no enzyme activity. Our findings suggest that genetic testing coupled with noninvasive ceramide analyses using tape-stripped stratum corneum samples might be useful for the early and precise diagnosis of congenital ichthyoses, including SHCB.

DOI： 10.1016/j.jlr.2022.100308

経過観察中に水疱性類天疱瘡を発症した、MV遺伝子変異を有する高齢発症の汗孔角化症の2例

有沢友希, 武市拓也, 伊藤靖敏, 棚橋華奈, 室慶直, 荻朋男, 秋山真志

加齢皮膚医学セミナー 17 巻 ( 2 ) 頁： 65 - 66 2022年12月

Global landscape of replicative DNA polymerase usage in the human genome 国際誌

Koyanagi Eri, Kakimoto Yoko, Minamisawa Tamiko, Yoshifuji Fumiya, Natsume Toyoaki, Higashitani Atsushi, Ogi Tomoo, Carr Antony M., Kanemaki Masato T., Daigaku Yasukazu

NATURE COMMUNICATIONS 13 巻 ( 1 ) 頁： 7221 - 7221 2022年11月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Nature Communications

The division of labour among DNA polymerase underlies the accuracy and efficiency of replication. However, the roles of replicative polymerases have not been directly established in human cells. We developed polymerase usage sequencing (Pu-seq) in HCT116 cells and mapped Polε and Polα usage genome wide. The polymerase usage profiles show Polε synthesises the leading strand and Polα contributes mainly to lagging strand synthesis. Combining the Polε and Polα profiles, we accurately predict the genome-wide pattern of fork directionality plus zones of replication initiation and termination. We confirm that transcriptional activity contributes to the pattern of initiation and termination and, by separately analysing the effect of transcription on co-directional and converging forks, demonstrate that coupled DNA synthesis of leading and lagging strands is compromised by transcription in both co-directional and convergent forks. Polymerase uncoupling is particularly evident in the vicinity of large genes, including the two most unstable common fragile sites, FRA3B and FRA3D, thus linking transcription-induced polymerase uncoupling to chromosomal instability. Together, our result demonstrated that Pu-seq in human cells provides a powerful and straightforward methodology to explore DNA polymerase usage and replication fork dynamics.

DOI： 10.1038/s41467-022-34929-8

Aicardi-Goutieres syndrome with SAMHD1 deficiency can be diagnosed by unscheduled DNA synthesis test 国際誌

Senju Chikako, Nakazawa Yuka, Shimada Mayuko, Iwata Dai, Matsuse Michiko, Tanaka Katsumi, Miyazaki Yasushi, Moriwaki Shinichi, Mitsutake Norisato, Ogi Tomoo

FRONTIERS IN PEDIATRICS 10 巻頁： 1048002 - 1048002 2022年11月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Frontiers in Pediatrics

Aicardi–Goutières syndrome (AGS) is a rare genetic disorder characterised by progressive encephalopathy, involving microcephaly, intracranial calcification, and cerebrospinal fluid lymphocytosis with increased interferon-α concentrations. The clinical features of AGS overlap with fetal cerebral anomalies caused by congenital infections, such as TORCH (toxoplasmosis, other, rubella, cytomegalovirus, and herpes), or with those of other genetic disorders showing neonatal microcephaly, including Cockayne syndrome (CS) with transcription-coupled DNA repair deficiency, and Seckel syndrome (SS) showing aberrant cell-cycle checkpoint signaling. Therefore, a differential diagnosis to confirm the genetic cause or a proof of infection should be considered. In this report, we describe an individual who showed primordial dwarfism and encephalopathy, and whose initial diagnosis was CS. First, we conducted conventional DNA repair proficiency tests for the patient derived fibroblast cells. Transcription-coupled nucleotide excision repair (TC-NER) activity, which is mostly compromised in CS cases, was slightly reduced in the patient's cells. However, unscheduled DNA synthesis (UDS) was significantly diminished. These cellular traits were inconsistent with the diagnosis of CS. We further performed whole exome sequencing for the case and identified a compound heterozygous loss-of-function variants in the SAMHD1 gene, mutations in which are known to cause AGS. As SAMHD1 encodes deoxyribonucleoside triphosphate triphosphohydrolase, we reasoned that the deoxyribonucleoside triphosphate (dNTP) pool size in the patient's cells was elevated, and the labeling efficiency of UDS-test was hindered due to the reduced concentration of phosphorylated ethynyl deoxyuridine (EdU), a nucleoside analogue used for the assay. In conclusion, UDS assay may be a useful diagnostic tool to distinguish between AGS with SAMHD1 mutations and other related diseases.

DOI： 10.3389/fped.2022.1048002

Performance of Nanopore and Illumina Metagenomic Sequencing for Pathogen Detection and Transcriptome Analysis in Infantile Central Nervous System Infections

Horiba Kazuhiro, Torii Yuka, Aizawa Yuta, Yamaguchi Makoto, Haruta Kazunori, Okumura Toshihiko, Suzuki Takako, Kawano Yoshihiko, Kawada Jun-ichi, Hara Shinya, Saitoh Akihiko, Giske Christian G., Ogi Tomoo, Ito Yoshinori

OPEN FORUM INFECTIOUS DISEASES 9 巻 ( 10 ) 頁： ofac504 2022年10月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Open Forum Infectious Diseases

Background: Infantile central nervous system infections (CNSIs) can be life-threatening and cause severe sequelae. However, the causative microorganism remains unknown in >40% of patients with aseptic infections. This study aimed to analyze the metagenome for detection of pathogens and the transcriptome for host immune responses during infection in a single cerebrospinal fluid (CSF) sample using 2 different next-generation sequencing (NGS) platforms, Nanopore and Illumina. Methods: Twenty-eight CNSIs patients (<12 months) were enrolled, and 49 clinical samples (28 CSF and 21 blood) were collected. The DNA extracted from all 49 samples was sequenced using the Illumina sequencer for the detection of pathogens. Extracted RNA was obtained in sufficient quantities from 23 CSF samples and subjected to sequencing on both Nanopore and Illumina platforms. Human-derived reads subtracted during pathogen detection were used for host transcriptomic analysis from both Nanopore and Illumina sequencing. Results: RNA metagenomic sequencing using both sequencing platforms revealed putative viral pathogens in 10 cases. DNA sequencing using the Illumina sequencer detected 2 pathogens. The results of Nanopore and Illumina RNA sequencing were consistent; however, the mapping coverage and depth to the detected pathogen genome of Nanopore RNA sequencing were greater than those of Illumina. Host transcriptomic analysis of Nanopore sequencing revealed highly expressed genes related to the antiviral roles of innate immunity from pathogen-identified cases. Conclusions: The use of Nanopore RNA sequencing for metagenomic diagnostics of CSF samples should help to elucidate both pathogens and host immune responses of CNSI and could shed light on the pathogenesis of these infections.

DOI： 10.1093/ofid/ofac504

Metabolome and transcriptome analysis on muscle of sporadic inclusion body myositis

Murakami Ayuka, Noda Seiya, Kazuta Tomoyuki, Hirano Satoko, Kimura Seigo, Nakanishi Hirotaka, Matsuo Koji, Tsujikawa Koyo, Iida Madoka, Koike Haruki, Sakamoto Kazuma, Hara Yuichiro, Kuru Satoshi, Kadomatsu Kenji, Shimamura Teppei, Ogi Tomoo, Katsuno Masahisa

ANNALS OF CLINICAL AND TRANSLATIONAL NEUROLOGY 9 巻 ( 10 ) 頁： 1602 - 1615 2022年10月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Annals of Clinical and Translational Neurology

Objective: Sporadic inclusion body myositis (sIBM) is the most common acquired myopathy in patients older than 50 years of age. sIBM is hardly responds to any immunosuppressing theraphies, and its pathophysiology remains elusive. This study aims to explore pathogenic pathways underlying sIBM and identify novel therapeutic targets using metabolomic and transcriptomic analyses. Methods: In this retrospective observational study, we analyzed biopsied muscle samples from 14 sIBM patients and six non-diseased subjects to identify metabolic profiles. Frozen muscle samples were used to measure metabolites with cation and anion modes of capillary electrophoresis time of flight mass spectrometry. We validated the metabolic pathway altered in muscles of sIBM patients through RNA sequencing and histopathological studies. Results: A total of 198 metabolites were identified. Metabolomic and transcriptomic analyses identified specific metabolite changes in sIBM muscle samples. The pathways of histamine biosynthesis and certain glycosaminoglycan biosynthesis were upregulated in sIBM patients, whereas those of carnitine metabolism and creatine metabolism were downregulated. Histopathological examination showed infiltration of mast cells and deposition of chondroitin sulfate in skeletal muscle samples, supporting the results of metabolomic and transcriptomic analyses. Interpretation: We identified alterations of several metabolic pathways in muscle samples of sIBM patients. These results suggest that mast cells, chondroitin sulfate biosynthesis, carnitine, and creatine play roles in sIBM pathophysiology.

DOI： 10.1002/acn3.51657

Six years’ accomplishment of the Initiative on Rare and Undiagnosed Diseases: nationwide project in Japan to discover causes, mechanisms, and cures

Takahashi Y., Date H., Oi H., Adachi T., Imanishi N., Kimura E., Takizawa H., Kosugi S., Matsumoto N., Kosaki K., Matsubara Y., Ando Y., Anzai T., Ariga T., Fukushima Y., Furusawa Y., Ganaha A., Goto Y., Hata K., Honda M., Iijima K., Ikka T., Imoto I., Kaname T., Kobayashi M., Kojima S., Kurahashi H., Kure S., Kurosawa K., Maegaki Y., Makita Y., Morio T., Narita I., Nomura F., Ogata T., Ozono K., Oka A., Okamoto N., Saitoh S., Sakurai A., Takada F., Takahashi T., Tamaoka A., Umezawa A., Yachie A., Yoshiura K., Chinen Y., Eguchi M., Fujio K., Hosoda K., Ichikawa T., Kawarai T., Kosho T., Masuno M., Nakamura A., Nakane T., Ogi T., Okada S., Sakata Y., Seto T., Takahashi Y., Takano T., Ueda M., Yagasaki H., Yamamoto T., Watanabe A., Hotta Y., Kubo A., Maruyama H., Moriyama K., Nanba E., Sakai N., Sekijima Y., Shimosegawa T., Takeuchi T., Usami S., Yamamoto K., Mizusawa H.

Journal of Human Genetics 67 巻 ( 9 ) 頁： 505 - 513 2022年9月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Journal of Human Genetics

The identification of causative genetic variants for hereditary diseases has revolutionized clinical medicine and an extensive collaborative framework with international cooperation has become a global trend to understand rare disorders. The Initiative on Rare and Undiagnosed Diseases (IRUD) was established in Japan to provide accurate diagnosis, discover causes, and ultimately provide cures for rare and undiagnosed diseases. The fundamental IRUD system consists of three pillars: IRUD diagnostic coordination, analysis centers (IRUD-ACs), and a data center (IRUD-DC). IRUD diagnostic coordination consists of clinical centers (IRUD-CLs) and clinical specialty subgroups (IRUD-CSSs). In addition, the IRUD coordinating center (IRUD-CC) manages the entire IRUD system and temporarily operates the IRUD resource center (IRUD-RC). By the end of March 2021, 6301 pedigrees consisting of 18,136 individuals were registered in the IRUD. The whole-exome sequencing method was completed in 5136 pedigrees, and a final diagnosis was established in 2247 pedigrees (43.8%). The total number of aberrated genes and pathogenic variants was 657 and 1718, among which 1113 (64.8%) were novel. In addition, 39 novel disease entities or phenotypes with 41 aberrated genes were identified. The 6-year endeavor of IRUD has been an overwhelming success, establishing an all-Japan comprehensive diagnostic and research system covering all geographic areas and clinical specialties/subspecialties. IRUD has accurately diagnosed diseases, identified novel aberrated genes or disease entities, discovered many candidate genes, and enriched phenotypic and pathogenic variant databases. Further promotion of the IRUD is essential for determining causes and developing cures for rare and undiagnosed diseases.

DOI： 10.1038/s10038-022-01025-0

A novel ZC4H2 variant in a female with severe respiratory complications

Wakabayashi Tomohiro, Mizukami Miyako, Terada Kojiro, Ishikawa Aki, Hinotsu Shiro, Kobayashi Masaki, Kato Koji, Ogi Tomoo, Tsugawa Takeshi, Sakurai Akihiro

BRAIN & DEVELOPMENT 44 巻 ( 8 ) 頁： 571 - 577 2022年9月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Brain and Development

Introduction: An X-linked ZC4H2 variant is associated with a variety of phenotypes that have abnormalities related to external malformation and neurodevelopment. There have been no reports on severe respiratory dysfunction resulting in surgical treatments not being possible due to the deformity resulting from in this disease. Here we report a female with arthrogryposis multiplex congenita with a severe respiratory complication. Case: A two-year-old girl had arthrogryposis multiplex congenita at delivery and subsequently had hypotonia and feeding difficulty. A novel ZC4H2 frameshift variant was identified by whole-exome sequencing in her genome. At eight months, she had recurrent aspiration pneumonia. A tracheostomy and gastrostomy were required; however, surgical intervention was not possible because of her short neck and complicated airway. Conclusion: We compared this case with previous reports. The truncation group had more described phenotypes than the non-truncation group. The patient had the most severe respiratory dysfunction in truncating variant.

DOI： 10.1016/j.braindev.2022.04.009

Ceramide profiling of stratum corneum in Sj?gren-Larsson syndrome 査読有り国際誌

Arai Ayami, Takeichi Takuya, Wakamoto Hiroyuki, Sassa Takayuki, Ito Yasutoshi, Murase Yuya, Ogi Tomoo, Akiyama Masashi, Kihara Akio

JOURNAL OF DERMATOLOGICAL SCIENCE 107 巻 ( 3 ) 頁： 114 - 122 2022年9月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Journal of Dermatological Science

Background: Sjögren–Larsson syndrome (SLS) is a neurocutaneous disorder whose causative gene is the fatty aldehyde dehydrogenase ALDH3A2 and of which ichthyosis is the major skin symptom. The stratum corneum contains a variety of ceramides, among which ω-O-acylceramides (acylceramides) and protein-bound ceramides are essential for skin permeability barrier formation. Objectives: To determine the ceramide classes/species responsible for SLS pathogenesis and the enzymes that are impaired in SLS. Methods: Genomic DNA was collected from peripheral blood samples from an SLS patient and her parents, and whole-genome sequencing and Sanger sequencing were performed. Lipids were extracted from stratum corneum samples from the SLS patient and healthy volunteers and subjected to ceramide profiling via liquid chromatography coupled with tandem mass spectrometry. Results: A duplication (c.55_130dup) and a missense mutation (p.Lys447Glu) were found in the patient's ALDH3A2 gene. The patient had reduced levels of all acylceramide classes, with total acylceramide levels at 25 % of healthy controls. Reductions were also observed for several nonacylated ceramides: ceramides with phytosphingosine or 6-hydroxysphingosine in the long-chain base moiety were reduced to 24 % and 41 % of control levels, respectively, and ceramides with an α-hydroxy fatty acid as the fatty acid moiety were reduced to 29 %. The fatty acid moiety was shortened in many nonacylated ceramide classes. Conclusion: These results suggest that reduced acylceramide levels are a primary cause of the ichthyosis symptoms of SLS, but reductions in other ceramide classes may also be involved.

DOI： 10.1016/j.jdermsci.2022.08.003

Whole-exome analysis of 177 pediatric patients with undiagnosed diseases

Narita Kotaro, Muramatsu Hideki, Narumi Satoshi, Nakamura Yuji, Okuno Yusuke, Suzuki Kyogo, Hamada Motoharu, Yamaguchi Naoya, Suzuki Atsushi, Nishio Yosuke, Shiraki Anna, Yamamori Ayako, Tsumura Yusuke, Sawamura Fumi, Kawaguchi Masahiro, Wakamatsu Manabu, Kataoka Shinsuke, Kato Kohji, Asada Hideyuki, Kubota Tetsuo, Muramatsu Yukako, Kidokoro Hiroyuki, Natsume Jun, Mizuno Seiji, Nakata Tomohiko, Inagaki Hidehito, Ishihara Naoko, Yonekawa Takahiro, Okumura Akihisa, Ogi Tomoo, Kojima Seiji, Kaname Tadashi, Hasegawa Tomonobu, Saitoh Shinji, Takahashi Yoshiyuki

SCIENTIFIC REPORTS 12 巻 ( 1 ) 頁： 14589 2022年8月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Scientific Reports

Recently, whole-exome sequencing (WES) has been used for genetic diagnoses of patients who remain otherwise undiagnosed. WES was performed in 177 Japanese patients with undiagnosed conditions who were referred to the Tokai regional branch of the Initiative on Rare and Undiagnosed Diseases (IRUD) (TOKAI-IRUD). This study included only patients who had not previously received genome-wide testing. Review meetings with specialists in various medical fields were held to evaluate the genetic diagnosis in each case, which was based on the guidelines of the American College of Medical Genetics and Genomics. WES identified diagnostic single-nucleotide variants in 66 patients and copy number variants (CNVs) in 11 patients. Additionally, a patient was diagnosed with Angelman syndrome with a complex clinical phenotype upon detection of a paternally derived uniparental disomy (UPD) [upd(15)pat] wherein the patient carried a homozygous DUOX2 p.E520D variant in the UPD region. Functional analysis confirmed that this DUOX2 variant was a loss-of-function missense substitution and the primary cause of congenital hypothyroidism. A significantly higher proportion of genetic diagnoses was achieved compared to previous reports (44%, 78/177 vs. 24–35%, respectively), probably due to detailed discussions and the higher rate of CNV detection.

DOI： 10.1038/s41598-022-14161-6

Exome sequencing analysis of Japanese autism spectrum disorder case-control sample supports an increased burden of synaptic function-related genes

Kimura Hiroki, Nakatochi Masahiro, Aleksic Branko, Guevara James, Toyama Miho, Hayashi Yu, Kato Hidekazu, Kushima Itaru, Morikawa Mako, Ishizuka Kanako, Okada Takashi, Tsurusaki Yoshinori, Fujita Atsushi, Miyake Noriko, Ogi Tomoo, Takata Atsushi, Matsumoto Naomichi, Buxbaum Joseph, Ozaki Norio, Sebat Jonathan

TRANSLATIONAL PSYCHIATRY 12 巻 ( 1 ) 頁： 265 2022年7月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Translational Psychiatry

Autism spectrum disorder (ASD) is a highly heritable, complex disorder in which rare variants contribute significantly to disease risk. Although many genes have been associated with ASD, there have been few genetic studies of ASD in the Japanese population. In whole exomes from a Japanese ASD sample of 309 cases and 299 controls, rare variants were associated with ASD within specific neurodevelopmental gene sets, including highly constrained genes, fragile X mental retardation protein target genes, and genes involved in synaptic function, with the strongest enrichment in trans-synaptic signaling (p = 4.4 × 10−4, Q-value = 0.06). In particular, we strengthen the evidence regarding the role of ABCA13, a synaptic function-related gene, in Japanese ASD. The overall results of this case-control exome study showed that rare variants related to synaptic function are associated with ASD susceptibility in the Japanese population.

DOI： 10.1038/s41398-022-02033-6

The iodide transporter Slc26a7 impacts thyroid function more strongly than Slc26a4 in mice

Yamaguchi Naoya, Suzuki Atsushi, Yoshida Aya, Tanaka Tatsushi, Aoyama Kohei, Oishi Hisashi, Hara Yuichiro, Ogi Tomoo, Amano Izuki, Kameo Satomi, Koibuchi Noriyuki, Shibata Yasuhiro, Ugawa Shinya, Mizuno Haruo, Saitoh Shinji

SCIENTIFIC REPORTS 12 巻 ( 1 ) 頁： 11259 2022年7月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Scientific Reports

SLC26A4 is a known iodide transporter, and is localized at the apical membrane of thyrocytes. Previously, we reported that SLC26A7 is also involved in iodide transport and that Slc26a7 is a novel causative gene for congenital hypothyroidism. However, its detailed role in vivo remains to be elucidated. We generated mice that were deficient in Slc26a7 and Slc26a4 to delineate differences and associations in their roles in iodide transport. Slc26a7−/− mice showed goitrous congenital hypothyroidism and mild growth failure on a normal diet. Slc26a7−/− mice with a low iodine environment showed marked growth failure. In contrast, Slc26a4−/− mice showed no growth failure and hypothyroidism in the same low iodine environment. Double-deficient mice showed more severe growth failure than Slc26a7−/− mice. RNA-seq analysis revealed that the number of differentially expressed genes (DEGs) in Slc26a7−/− mice was significantly higher than that in Slc26a4−/− mice. These indicate that SLC26A7 is more strongly involved in iodide transport and the maintenance of thyroid function than SLC26A4.

DOI： 10.1038/s41598-022-15151-4

Case of ichthyosis with confetti caused by KRT10 mutation, complicated with multiple malignant melanomas 国際誌

Ito Yasutoshi, Takeichi Takuya, Nakagawa Koichi, Tanahashi Kana, Muro Yoshinao, Ogi Tomoo, Akiyama Masashi

JOURNAL OF DERMATOLOGY 49 巻 ( 7 ) 頁： E228 - E229 2022年7月

Deep Phenotyping of Superficial Epidermolytic Ichthyosis due to a Recurrent Mutation in KRT2 国際誌

Suzuki Yuika, Takeichi Takuya, Tanahashi Kana, Muro Yoshinao, Suga Yasushi, Ogi Tomoo, Akiyama Masashi

INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES 23 巻 ( 14 ) 2022年7月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：International Journal of Molecular Sciences

Superficial epidermolytic ichthyosis (SEI) is an autosomal dominant inherited ichthyosis. SEI is caused by mutations in KRT2 and frequently shows erythroderma and widespread blistering at birth. We report the clinical manifestations of two patients from a Japanese family with SEI caused by a hotspot mutation, p.Glu487Lys, in KRT2. In addition, we summarize previous reports on SEI patients with the identical mutation. One of the two patients had disease onset at the age of 7 months. The other patient’s age of onset is unknown, but it was in childhood. Neither of the two patients showed erythroderma. To perform deep phenotyping, we studied the age of onset and the frequency of erythroderma in 34 reported SEI cases with the p.Glu487Lys mutation, including the present cases. Among the cases with sufficient clinical information, 44.4% of the cases that were due to p.Glu487Lys in KRT2 occurred at birth. Erythroderma was observed in 11.1% of the cases with p.Glu487Lys in KRT2.

DOI： 10.3390/ijms23147791

Detection of antiviral drug resistance in patients with congenital cytomegalovirus infection using long-read sequencing: a retrospective observational study

Torii Yuka, Horiba Kazuhiro, Kawada Jun-ichi, Haruta Kazunori, Yamaguchi Makoto, Suzuki Takako, Uryu Hideko, Kashiwa Naoyuki, Goishi Keiji, Ogi Tomoo, Ito Yoshinori

BMC INFECTIOUS DISEASES 22 巻 ( 1 ) 頁： 568 2022年6月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：BMC Infectious Diseases

Background: Congenital human cytomegalovirus (cCMV) infection can cause sensorineural hearing loss and neurodevelopmental disabilities in children. Ganciclovir and valganciclovir (GCV/VGCV) improve long-term audiologic and neurodevelopmental outcomes for patients with cCMV infection; however, antiviral drug resistance has been documented in some cases. Long-read sequencing can be used for the detection of drug resistance mutations. The objective of this study was to develop full-length analysis of UL97 and UL54, target genes with mutations that confer GCV/VGCV resistance using long-read sequencing, and investigate drug resistance mutation in patients with cCMV infection. Methods: Drug resistance mutation analysis was retrospectively performed in 11 patients with cCMV infection treated with GCV/VGCV. UL97 and UL54 genes were amplified using blood DNA. The amplicons were sequenced using a long-read sequencer and aligned with the reference gene. Single nucleotide variants were detected and replaced with the reference sequence. The replaced sequence was submitted to a mutation resistance analyzer, which is an open platform for drug resistance mutations. Results: Two drug resistance mutations (UL54 V823A and UL97 A594V) were found in one patient. Both mutations emerged after 6 months of therapy, where viral load increased. Mutation rates subsided after cessation of GCV/VGCV treatment. Conclusions: Antiviral drug resistance can emerge in patients with cCMV receiving long-term therapy. Full-length analysis of UL97 and UL54 via long-read sequencing enabled the rapid and comprehensive detection of drug resistance mutations.

DOI： 10.1186/s12879-022-07537-6

Expanding the phenotypic spectrum of ARCN1-related syndrome

Ritter Alyssa L., Gold Jessica, Hayashi Hiroshi, Ackermann Amanda M., Hanke Stephanie, Skraban Cara, Cuddapah Sanmati, Bhoj Elizabeth, Li Dong, Kuroda Yukiko, Wen Jessica, Takeda Ryojun, Bibb Audrey, El Chehadeh Salima, Piton Amelie, Ohl Jeanine, Kukolich Mary K., Nagasaki Keisuke, Kato Kohji, Ogi Tomoo, Bhatti Tricia, Russo Pierre, Krock Bryan, Murrell Jill R., Sullivan Jennifer A., Shashi Vandana, Stong Nicholas, Hakonarson Hakon, Sawano Kentaro, Torti Erin, Willaert Rebecca, Si Yue, Wilcox William Ross, Wirgenes Katrine Verena, Thomassen Kristian, Carlotti Katherine, Erwin Angelika, Lazier Joanna, Marquardt Thorsten, He Miao, Edmondson Andrew C., Izumi Kosuke

GENETICS IN MEDICINE 24 巻 ( 6 ) 頁： 1227 - 1237 2022年6月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Genetics in Medicine

Purpose: This study aimed to describe the phenotypic and molecular characteristics of ARCN1-related syndrome. Methods: Patients with ARCN1 variants were identified, and clinician researchers were connected using GeneMatcher and physician referrals. Clinical histories were collected from each patient. Results: In total, we identified 14 cases of ARCN1-related syndrome, (9 pediatrics, and 5 fetal cases from 3 families). The clinical features these newly identified cases were compared to 6 previously reported cases for a total of 20 cases. Intrauterine growth restriction, micrognathia, and short stature were present in all patients. Other common features included prematurity (11/15, 73.3%), developmental delay (10/14, 71.4%), genitourinary malformations in males (6/8, 75%), and microcephaly (12/15, 80%). Novel features of ARCN1-related syndrome included transient liver dysfunction and specific glycosylation abnormalities during illness, giant cell hepatitis, hepatoblastoma, cataracts, and lethal skeletal manifestations. Developmental delay was seen in 73% of patients, but only 3 patients had intellectual disability, which is less common than previously reported. Conclusion: ARCN1-related syndrome presents with a wide clinical spectrum ranging from a severe embryonic lethal syndrome to a mild syndrome with intrauterine growth restriction, micrognathia, and short stature without intellectual disability. Patients with ARCN1-related syndrome should be monitored for liver dysfunction during illness, cataracts, and hepatoblastoma. Additional research to further define the phenotypic spectrum and possible genotype–phenotype correlations are required.

DOI： 10.1016/j.gim.2022.02.005

経過観察中に水疱性類天疱瘡を発症した、MV遺伝子変異を有する高齢発症の汗孔角化症の2例

有沢友希, 武市拓也, 伊藤靖敏, 棚橋華奈, 室慶直, 荻朋男, 秋山真志

加齢皮膚医学セミナー 17 巻 ( 1 ) 頁： 74 - 75 2022年6月

経過観察中に水疱性類天疱瘡を発症した、MV遺伝子変異を有する高齢発症の汗孔角化症の2例

有沢友希, 武市拓也, 伊藤靖敏, 棚橋華奈, 室慶直, 荻朋男, 秋山真志

加齢皮膚医学セミナー 17 巻 ( 1 ) 頁： 74 - 75 2022年6月

Epithelioid cell granuloma formation in CARD14-associated papulosquamous eruptions 国際誌

Takeichi T., Ikeda K., Muro Y., Ogi T., Morizane S., Akiyama M.

JOURNAL OF THE EUROPEAN ACADEMY OF DERMATOLOGY AND VENEREOLOGY 36 巻 ( 5 ) 頁： E369 - E371 2022年5月

Germline variants in tumor suppressor FBXW7 lead to impaired ubiquitination and a neurodevelopmental syndrome

Stephenson Sarah E. M., Costain Gregory, Blok Laura E. R., Silk Michael A., Nguyen Thanh Binh, Dong Xiaomin, Alhuzaimi Dana E., Dowling James J., Walker Susan, Amburgey Kimberly, Hayeems Robin Z., Rodan Lance H., Schwartz Marc A., Picker Jonathan, Lynch Sally A., Gupta Aditi, Rasmussen Kristen J., Schimmenti Lisa A., Klee Eric W., Niu Zhiyv, Agre Katherine E., Chilton Ilana, Chung Wendy K., Revah-Politi Anya, Au P. Y. Billie, Griffith Christopher, Racobaldo Melissa, Raas-Rothschild Annick, Ben Zeev Bruria, Barel Ortal, Moutton Sebastien, Morice-Picard Fanny, Carmignac Virginie, Cornaton Jenny, Marle Nathalie, Devinsky Orrin, Stimach Chandler, Wechsler Stephanie Burns, Hainline Bryan E., Sapp Katie, Willems Marjolaine, Bruel Angeline, Dias Kerith-Rae, Evans Carey-Anne, Roscioli Tony, Sachdev Rani, Temple Suzanna E. L., Zhu Ying, Baker Joshua J., Scheffer Ingrid E., Gardiner Fiona J., Schneider Amy L., Muir Alison M., Mefford Heather C., Crunk Amy, Heise Elizabeth M., Millan Francisca, Monaghan Kristin G., Person Richard, Rhodes Lindsay, Richards Sarah, Wentzensen Ingrid M., Cogne Benjamin, Isidor Bertrand, Nizon Mathilde, Vincent Marie, Besnard Thomas, Piton Amelie, Marcelis Carlo, Kato Kohji, Koyama Norihisa, Ogi Tomoo, Goh Elaine Suk-Ying, Richmond Christopher, Amor David J., Boyce Jessica O., Morgan Angela T., Hildebrand Michael S., Kaspi Antony, Bahlo Melanie, Fridriksdottir Run, Katrinardottir Hildigunnur, Sulem Patrick, Stefansson Kari, Bjornsson Hans Tomas, Mandelstam Simone, Morleo Manuela, Mariani Milena, Scala Marcello, Accogli Andrea, Torella Annalaura, Capra Valeria, Wallis Mathew, Jansen Sandra, Waisfisz Quinten, de Haan Hugoline, Sadedin Simon, Lim Sze Chern, White Susan M., Ascher David B., Schenck Annette, Lockhart Paul J., Christodoulou John, Tan Tiong Yang

AMERICAN JOURNAL OF HUMAN GENETICS 109 巻 ( 4 ) 頁： 601 - 617 2022年4月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：American Journal of Human Genetics

Neurodevelopmental disorders are highly heterogenous conditions resulting from abnormalities of brain architecture and/or function. FBXW7 (F-box and WD-repeat-domain-containing 7), a recognized developmental regulator and tumor suppressor, has been shown to regulate cell-cycle progression and cell growth and survival by targeting substrates including CYCLIN E1/2 and NOTCH for degradation via the ubiquitin proteasome system. We used a genotype-first approach and global data-sharing platforms to identify 35 individuals harboring de novo and inherited FBXW7 germline monoallelic chromosomal deletions and nonsense, frameshift, splice-site, and missense variants associated with a neurodevelopmental syndrome. The FBXW7 neurodevelopmental syndrome is distinguished by global developmental delay, borderline to severe intellectual disability, hypotonia, and gastrointestinal issues. Brain imaging detailed variable underlying structural abnormalities affecting the cerebellum, corpus collosum, and white matter. A crystal-structure model of FBXW7 predicted that missense variants were clustered at the substrate-binding surface of the WD40 domain and that these might reduce FBXW7 substrate binding affinity. Expression of recombinant FBXW7 missense variants in cultured cells demonstrated impaired CYCLIN E1 and CYCLIN E2 turnover. Pan-neuronal knockdown of the Drosophila ortholog, archipelago, impaired learning and neuronal function. Collectively, the data presented herein provide compelling evidence of an F-Box protein-related, phenotypically variable neurodevelopmental disorder associated with monoallelic variants in FBXW7.

DOI： 10.1016/j.ajhg.2022.03.002

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