並列タイトル等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
授与機関名Nagasaki University (長崎大学)
一般注記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)
著作権情報© 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.
関連情報http://hdl.handle.net/10069/00042236
関連情報（DOI）10.3389/fped.2022.1048002
連携機関・データベース国立情報学研究所 : 学術機関リポジトリデータベース（IRDB）（機関リポジトリ）