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

Overview

Journal Am J Hum Genet

Publisher Cell Press

Specialty Genetics

Date 2020 Oct 6

PMID 33022220

Citations 31

Authors

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 Sisirak

Nora Almutairi

K C Allen Chan

Rossa W K Chiu

Boris Reizis

Y M Dennis Lo

Affiliations

Soon will be listed here.

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.

Citing Articles

Identification and functional characterisation of a novel DNASE1L3 variant (c.572A>G, p.Asn191Ser) in three Emirati families with systemic lupus erythematosus and hypocomplementaemic urticarial vasculitis.

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Expanded knowledge of cell-free DNA biology: potential to broaden the clinical utility.

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Analysis of a cell-free DNA-based cancer screening cohort links fragmentomic profiles, nuclease levels, and plasma DNA concentrations.

Malki Y, Kang G, Lam W, Lam W, Zhou Q, Cheng S Genome Res. 2024; 35(1):31-42.

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Cell-free DNA from germline TP53 mutation carriers reflect cancer-like fragmentation patterns.

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References

Jiang P, Chan C, Chan K, Cheng S, Wong J, Wong V . Lengthening and shortening of plasma DNA in hepatocellular carcinoma patients. Proc Natl Acad Sci U S A. 2015; 112(11):E1317-25. PMC: 4372002. DOI: 10.1073/pnas.1500076112. View

Li R, Yu C, Li Y, Lam T, Yiu S, Kristiansen K . SOAP2: an improved ultrafast tool for short read alignment. Bioinformatics. 2009; 25(15):1966-7. DOI: 10.1093/bioinformatics/btp336. View

Keyel P . Dnases in health and disease. Dev Biol. 2017; 429(1):1-11. PMC: 11492367. DOI: 10.1016/j.ydbio.2017.06.028. View

Chiu R, Akolekar R, Zheng Y, Leung T, Sun H, Chan K . Non-invasive prenatal assessment of trisomy 21 by multiplexed maternal plasma DNA sequencing: large scale validity study. BMJ. 2011; 342:c7401. PMC: 3019239. DOI: 10.1136/bmj.c7401. View

Davis M, Brewer J . Urticarial vasculitis and hypocomplementemic urticarial vasculitis syndrome. Immunol Allergy Clin North Am. 2004; 24(2):183-213, vi. DOI: 10.1016/j.iac.2004.01.007. View

Jahr S, Hentze H, Englisch S, Hardt D, Fackelmayer F, Hesch R . DNA fragments in the blood plasma of cancer patients: quantitations and evidence for their origin from apoptotic and necrotic cells. Cancer Res. 2001; 61(4):1659-65. View

Napirei M, Wulf S, Eulitz D, Mannherz H, Kloeckl T . Comparative characterization of rat deoxyribonuclease 1 (Dnase1) and murine deoxyribonuclease 1-like 3 (Dnase1l3). Biochem J. 2005; 389(Pt 2):355-64. PMC: 1175112. DOI: 10.1042/BJ20042124. View

Belot A, Rice G, Omarjee S, Rouchon Q, Smith E, Moreews M . Contribution of rare and predicted pathogenic gene variants to childhood-onset lupus: a large, genetic panel analysis of British and French cohorts. Lancet Rheumatol. 2024; 2(2):e99-e109. DOI: 10.1016/S2665-9913(19)30142-0. View

Thierry A, El Messaoudi S, Gahan P, Anker P, Stroun M . Origins, structures, and functions of circulating DNA in oncology. Cancer Metastasis Rev. 2016; 35(3):347-76. PMC: 5035665. DOI: 10.1007/s10555-016-9629-x. View

10.

Lisowski L, Tay S, Alexander I . Adeno-associated virus serotypes for gene therapeutics. Curr Opin Pharmacol. 2015; 24:59-67. DOI: 10.1016/j.coph.2015.07.006. View

11.

Lo Y, Chan K, Sun H, Chen E, Jiang P, Lun F . Maternal plasma DNA sequencing reveals the genome-wide genetic and mutational profile of the fetus. Sci Transl Med. 2010; 2(61):61ra91. DOI: 10.1126/scitranslmed.3001720. View

12.

Ozcakar Z, Foster 2nd J, Diaz-Horta O, Kasapcopur O, Fan Y, Yalcinkaya F . DNASE1L3 mutations in hypocomplementemic urticarial vasculitis syndrome. Arthritis Rheum. 2013; 65(8):2183-9. DOI: 10.1002/art.38010. View

13.

Jiang P, Sun K, Peng W, Cheng S, Ni M, Yeung P . Plasma DNA End-Motif Profiling as a Fragmentomic Marker in Cancer, Pregnancy, and Transplantation. Cancer Discov. 2020; 10(5):664-673. DOI: 10.1158/2159-8290.CD-19-0622. View

14.

Nabbi A, Riabowol K . Rapid Isolation of Nuclei from Cells In Vitro. Cold Spring Harb Protoc. 2015; 2015(8):769-72. DOI: 10.1101/pdb.prot083733. View

15.

Shiokawa D, Tanuma S . Characterization of human DNase I family endonucleases and activation of DNase gamma during apoptosis. Biochemistry. 2001; 40(1):143-52. DOI: 10.1021/bi001041a. View

16.

Batu E, Kosukcu C, Taskiran E, Sahin S, Akman S, Sozeri B . Whole Exome Sequencing in Early-onset Systemic Lupus Erythematosus. J Rheumatol. 2018; 45(12):1671-1679. DOI: 10.3899/jrheum.171358. View

17.

Pei X, He T, Hall N, Gerber D, Samulski R, Li C . AAV8 virions hijack serum proteins to increase hepatocyte binding for transduction enhancement. Virology. 2018; 518:95-102. PMC: 5911186. DOI: 10.1016/j.virol.2018.02.007. View

18.

Bruschi M, Bonanni A, Petretto A, Vaglio A, Pratesi F, Santucci L . Neutrophil Extracellular Traps Profiles in Patients with Incident Systemic Lupus Erythematosus and Lupus Nephritis. J Rheumatol. 2019; 47(3):377-386. PMC: 6917988. DOI: 10.3899/jrheum.181232. View

19.

Al-Mayouf S, Sunker A, Abdwani R, Al Abrawi S, Almurshedi F, Alhashmi N . Loss-of-function variant in DNASE1L3 causes a familial form of systemic lupus erythematosus. Nat Genet. 2011; 43(12):1186-8. DOI: 10.1038/ng.975. View

20.

Cohen J, Li L, Wang Y, Thoburn C, Afsari B, Danilova L . Detection and localization of surgically resectable cancers with a multi-analyte blood test. Science. 2018; 359(6378):926-930. PMC: 6080308. DOI: 10.1126/science.aar3247. View