Plasma DNA Profile Associated with DNASE1L3 Gene Mutations: Clinical Observations, Relationships to Nuclease Substrate Preference, and In Vivo Correction.
Am J Hum Genet
; 107(5): 882-894, 2020 11 05.
Article
em En
| MEDLINE
| ID: mdl-33022220
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.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
DNA
/
Endodesoxirribonucleases
/
Lúpus Eritematoso Sistêmico
/
Mutação
Tipo de estudo:
Observational_studies
/
Prognostic_studies
/
Risk_factors_studies
Aspecto:
Patient_preference
Limite:
Animals
/
Humans
Idioma:
En
Revista:
Am J Hum Genet
Ano de publicação:
2020
Tipo de documento:
Article
País de afiliação:
China