2025-11-21 東京大学,順天堂大学
本研究で実践された新しい診断支援スキーム
<関連情報>
- https://www.rcast.u-tokyo.ac.jp/ja/news/release/20251121.html
- https://www.frontiersin.org/journals/molecular-biosciences/articles/10.3389/fmolb.2025.1706392/full
診断上解決されていない個人において特定されたATP結合モチーフのDNA2変異
A DNA2 mutation in the ATP-binding motif identified in a diagnostically unresolved individual
Keisuke Saito,Yukiko Yatsuka,Ayuno Kawakami,Shinichiro Kumagaya,Nana Akiyama,Yasushi Okazaki,Kei Murayama,Hiroshi Ishikita
Frontiers in Molecular Biosciences Published:21 November 2025
DOI:https://doi.org/10.3389/fmolb.2025.1706392
Many individuals with chronic, medically unexplained symptoms remain without a diagnosis, despite extensive clinical evaluations. Here, we present a framework integrating genome analysis with protein structural analysis to investigate such a case. Genome sequencing of a diagnostically unresolved individual identified a previously unreported DNA2 missense variant: T652R. This mutation lies within the Walker A motif (GxxxxGKT) of the helicase 1A domain, at an “x” position in the P-loop critical for ATP recognition. Structural analysis revealed that the introduced Arg652 sidechain displaces the conserved Lys654 from its canonical ATP-binding role and forms a new salt bridge with Asp973 in the helicase domain 2A. This interaction likely locks DNA2 in a closed conformation, impairing the dynamic domain movement essential for helicase activity. The case presented here demonstrates how structure-guided analysis of even a single missense variant can provide a basis of understanding the molecular origin of symptoms and help maximize the often underutilized diagnostic potential of genome sequencing.
