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

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.

journal_name

Am J Hum Genet

authors

Chan RWY,Serpas L,Ni M,Volpi S,Hiraki LT,Tam LS,Rashidfarrokhi A,Wong PCH,Tam LHP,Wang Y,Jiang P,Cheng ASH,Peng W,Han DSC,Tse PPP,Lau PK,Lee WS,Magnasco A,Buti E,Sisirak V,AlMutairi N,Chan KCA,Chiu RWK,Reizi

doi

10.1016/j.ajhg.2020.09.006

subject

Has Abstract

pub_date

2020-11-05 00:00:00

pages

882-894

issue

5

eissn

0002-9297

issn

1537-6605

pii

S0002-9297(20)30326-8

journal_volume

107

pub_type

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