A DNA2 mutation in the ATP-binding motif identified in a diagnostically unresolved individual.

ABSTRACT: 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 dynami

SUBMITTER: Saito K 

PROVIDER: S-EPMC12678126 | biostudies-literature | 2025

REPOSITORIES: biostudies-literature