Plasma DNA Profile Associated with DNASE1L3 Gene Mutations: Clinical Observations, Relationships to Nuclease Substrate Preference, and In Vivo Correction

Rebecca W Y Chan, Lee Serpas, Meng Ni, Stefano Volpi, Linda T Hiraki, Lai-Shan Tam, Ali Rashidfarrokhi, Priscilla C H Wong, Lydia H P Tam, Yueyang Wang, Peiyong Jiang, Alice S H Cheng, Wenlei Peng, Diana S C Han, Patty P P Tse, Pik Ki Lau, Wing-Shan Lee, Alberto Magnasco, Elisa Buti, Vanja SisirakNora AlMutairi, K C Allen Chan, Rossa W K Chiu, Boris Reizis, Y M Dennis Lo

Research output: Contribution to journalArticlepeer-review

Abstract

Plasma DNA fragmentomics is an emerging area in cell-free DNA diagnostics and research. In murine models, it has been shown that the extracellular DNase, DNASE1L3, plays a role in the fragmentation of plasma DNA. In humans, DNASE1L3 deficiency causes familial monogenic systemic lupus erythematosus with childhood onset and anti-dsDNA reactivity. In this study, we found that human patients with DNASE1L3 disease-associated gene variations showed aberrations in size and a reduction of a "CC" end motif of plasma DNA. Furthermore, we demonstrated that DNA from DNASE1L3-digested cell nuclei showed a median length of 153 bp with CC motif frequencies resembling plasma DNA from healthy individuals. Adeno-associated virus-based transduction of Dnase1l3 into Dnase1l3-deficient mice restored the end motif profiles to those seen in the plasma DNA of wild-type mice. Our findings demonstrate that DNASE1L3 is an important player in the fragmentation of plasma DNA, which appears to act in a cell-extrinsic manner to regulate plasma DNA size and motif frequency.

Original languageEnglish
Pages (from-to)882-894
Number of pages13
JournalAmerican Journal of Human Genetics
Volume107
Issue number5
DOIs
Publication statusPublished - Nov 5 2020

Keywords

  • Animals
  • Case-Control Studies
  • DNA/blood
  • DNA Fragmentation
  • Dependovirus/genetics
  • Disease Models, Animal
  • Endodeoxyribonucleases/deficiency
  • Genetic Therapy
  • Genetic Vectors/chemistry
  • Humans
  • Lupus Erythematosus, Systemic/enzymology
  • Mice
  • Mice, Transgenic
  • Mutation
  • Substrate Specificity
  • Transduction, Genetic

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