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Brief Report: Deficiency of Complement 1r Subcomponent in Early‐Onset Systemic Lupus Erythematosus: The Role of Disease‐Modifying Alleles in a Monogenic Disease
Author(s) -
Demirkaya Erkan,
Zhou Qing,
Smith Carolyne K.,
Ombrello Michael J.,
Deuitch Natalie,
Tsai Wanxia L.,
Hoffmann Patrycja,
Remmers Elaine F.,
Takeuchi Masaki,
Park Yong Hwan,
Chae JaeJin,
Barut Kenan,
Simsek Dogan,
Adrovic Amra,
Sahin Sezgin,
Caliskan Salim,
Chandrasekharappa Settara C.,
Hasni Sarfaraz A.,
Ombrello Amanda K.,
Gadina Massimo,
Kastner Daniel L.,
Kaplan Mariana J.,
Kasapcopur Ozgur,
Aksentijevich Ivona
Publication year - 2017
Publication title -
arthritis and rheumatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.106
H-Index - 314
eISSN - 2326-5205
pISSN - 2326-5191
DOI - 10.1002/art.40158
Subject(s) - exome sequencing , immunology , haplotype , allele , genotyping , sanger sequencing , systemic lupus erythematosus , medicine , disease , genotype , biology , phenotype , mutation , genetics , gene
Objective To identify a genetic cause of early‐onset systemic lupus erythematosus (SLE) in a large consanguineous family from Turkey and to study the mechanisms of the disease. Methods We performed whole‐exome sequencing and single‐nucleotide polymorphism array genotyping in family members with and without SLE. Protein and gene expression, cytokine profile, neutrophil extracellular trap (NET) formation, and presence of low‐density granulocytes were evaluated in patient primary cells and serum samples. Results We identified a novel, homozygous, loss‐of‐function mutation (p.Pro445Leufs*11) in the C1R gene. Using the Sanger method of DNA sequencing in 14 family members, we confirmed the presence of the mutation in 4 patients with SLE and in an asymptomatic 9‐year‐old girl. Complement levels were low in sera from patients with truncated C1r protein. Two siblings with SLE who were available for detailed evaluation exhibited strong type I interferon (IFN) inflammatory signatures despite their disease being clinically inactive at the time of sampling. The type I IFN transcriptional signature in the patients’ blood correlated with disease expressivity, whereas the neutrophil signature in peripheral blood mononuclear cells was likely associated with disease severity. The female patient with SLE with the most severe phenotype presented with a stronger neutrophil signature, defined by enhanced NET formation and the presence of low‐density granulocytes. Analysis of exome data for modifying alleles suggested enrichment of common SLE‐associated variants in the more severely affected patients. Lupus‐associated HLA alleles or HLA haplotypes were not shared among the 4 affected subjects. Conclusion Our findings revealed a novel high‐penetrance mutation in C1R as the cause of monogenic SLE. Disease expressivity in this family appears to be influenced by additional common and rare genetic variants.