Aicardi–Goutières syndrome with SAMHD1 deficiency can be diagnosed by unscheduled DNA synthesis test

• Material Type: 博士論文
• Title: Aicardi–Goutières syndrome with SAMHD1 deficiency can be diagnosed by unscheduled DNA synthesis test
• Author/Editor: 千住 , 千佳子
• Author Heading: 千住 , 千佳子
• Publication, Distribution, etc.: Frontiers Media S.A.
• Publication Date: 2023-03-01
• Publication Date (W3CDTF): 2023-03-01
• Alternative Title: SAMHD1欠損症を伴うAicardi–Goutières症候群は不定期DNA合成試験によって診断できる
• Periodical title: Frontiers in Pediatrics
• No. or year of volume/issue: 10
• Volume: 10
• Pages: 1048002-
• ISSN (Periodical Title): ISSN : 2296-2360
• Degree grantor/type: Nagasaki University (長崎大学)
• Date Granted: 2023-03-01
• Dissertation Number: 甲医歯薬第1503号
• Degree Type: 博士(医学)
• Text Language Code: eng
• Subject Heading: Aicardi-Goutières syndrome (AGS); SAMHD1; unscheduled DNA synthesis (UDS); cockayne syndrome (CS); transcription coupled repair (TCR)
• Target Audience: 一般
• Note (General): 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 ranscriptioncoupled DNA repair deficiency, and Seckel syndrome (SS) showing aberrant cellcycle 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.; 長崎大学学位論文 学位記番号:博(医歯薬)甲第1503号 学位授与年月日:令和5年3月1日; Author: Chikako Senju, Yuka Nakazawa, Mayuko Shimada, Dai Iwata, Michiko Matsuse, Katsumi Tanaka, Yasushi Miyazaki, Shinichi Moriwaki, Norisato Mitsutake, Tomoo Ogi; Citation: Frontiers in Pediatrics, 10, art. no. 1048002; 2022; identifier:Nagasaki University (長崎大学), 博士(医学) (2023-03-01)
• Source: fulltext; https://nagasaki-u.repo.nii.ac.jp/?action=repository_action_common_download&item_id=28207&item_no=1&attribute_id=70&file_no=1
• Access Restrictions: インターネット公開
• Rights (production): © 2022 Senju, Nakazawa, Shimada, Iwata, Matsuse, Tanaka, Miyazaki, Moriwaki, Mitsutake and Ogi. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
• Related Material: http://hdl.handle.net/10069/00042236
• Related Material (DOI): 10.3389/fped.2022.1048002
• Data Provider (Database): 国立情報学研究所 : 学術機関リポジトリデータベース（IRDB）（機関リポジトリ）; https://irdb.nii.ac.jp
• Original Data Provider (Database): 長崎大学 : 長崎大学学術研究成果リポジトリ