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Loss-of-function variant in DNASE1L3 causes a familial form of systemic lupus erythematosus

Abstract

Systemic lupus erythematosus (SLE) is a complex autoimmune disease that causes substantial morbidity. As is typical for many other multifactorial disorders, much of the heritability of SLE remains unknown. We identified a rare autosomal recessive form of SLE, in which autozygome analysis revealed a null mutation in the DNASE1L3 gene. The DNASE1L3-related SLE we describe was always pediatric in onset and correlated with a high frequency of lupus nephritis. Our findings confirm the critical role of impaired clearance of degraded DNA in SLE pathogenesis.

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Figure 1: Identification of a new inactivating mutation in DNASE1L3 in a Mendelian phenocopy of SLE.

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Acknowledgements

We would like to thank the families for their participation and the Genotyping and Sequencing Core Facilities at King Faisal Specialist Hospital and Research Center for their technical help. This work is supported by a Dubai Harvard Foundation for Medical Research collaborative grant (FSA).

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The study was conceived of by S.M.A.-M., F.A., M.A.-O., L.A.-J. and F.S.A. Data were collected by S.M.A.-M., A.S., R.A., S.A.A., F.A., N.A., A.A.-S., W.S., A.Q., E.A., M.A.-O., S.A.M., H.A.-R., M.H., L.A.-J. and F.S.A. Data analysis was performed by A.S., R.A., H.K., L.A.-J. and F.S.A. The manuscript was written by F.S.A. and edited by S.M.A.-M., A.S., R.A., S.A.A., F.A., N.A. and L.A.-J.

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Correspondence to Fowzan S Alkuraya.

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The authors declare no competing financial interests.

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Supplementary Methods, Supplementary Figures 1–3 and Supplementary Table 1 (PDF 917 kb)

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Al-Mayouf, S., Sunker, A., Abdwani, R. et al. Loss-of-function variant in DNASE1L3 causes a familial form of systemic lupus erythematosus. Nat Genet 43, 1186–1188 (2011). https://doi.org/10.1038/ng.975

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