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Systemic lupus erythematosus (SLE) is a chronic autoimmune disease with familial aggregation and a strong genetic predisposition. Geng et al 1 recently identified the hypomorphic loss-of-function variant of neutrophil cytosolic factor 1 (NCF1), Arg90His is causal for SLE, which established the key roles of reactive oxygen species (ROS) signalling pathway in SLE. Consistent results were also reported by Meng et al.2 Intriguingly, we found a novel heterozygous mutation of the transient receptor potential channel 6 (TRPC6) gene, an NCF1-ROS downstream calcium channel (NCF1-ROS-TRPC6) activated by diacylglycerol,3–5 and it acts as a loss-of-function mutation in an SLE family.
The clinical and laboratory features of the three members diagnosed with SLE in the family are shown in table 1. All three members had rash, arthritis, strong positive antinuclear and anti-double-stranded DNA (dsDNA) antibodies and fulfilled the EULAR/American College of Rheumatology criteria for SLE. We performed whole exome sequencing in five family members (figure 1A) to determine the possible disease-causing mutation, and variant analysis (figure 1B) revealed a heterozygous frameshift mutation in TRPC6 (c.1891-1894delGTCA; p.Val631fs). Sanger sequencing of this variant in the five members indicated segregation with SLE. The female predominance in our SLE family with the TRPC6-Val631fs mutation and in the NCF1-Arg90His knock-in mouse models developed by Geng et al was presumably due to the relatively stronger X-linked-TLR7/MyD88 signalling and interferon production in female …
Handling editor Josef S Smolen
DC and HY contributed equally.
Correction notice This article has been corrected since it published Online First. The ORCID details for Liangjing Lu has been amended.
Contributors DC and HY collected the medical records of the patients and wrote the manuscript. DC performed the experiments. LZ analysed the gene mutation. LL and FL supervised the study and edited the manuscript.
Funding This study was funded by the National Key Research and Development Programme of China (grant no: 2017YFC0909002), the National Natural Science Foundation of China (grant no: 81974251), and the Innovative research team of high-level local universities in Shanghai (SHSMU-ZDCX20210600).
Competing interests None declared.
Patient and public involvement Patients and/or the public were not involved in the design, conduct, reporting or dissemination plans of this research.
Provenance and peer review Not commissioned; externally peer reviewed.