C1S and Systemic Lupus Erythematosus

C1S, a critical component of the classical complement pathway, has been strongly implicated in the pathogenesis of systemic lupus erythematosus (SLE). Multiple independent studies have identified rare homozygous and compound heterozygous mutations in C1S (HGNC:1247) in patients with early-onset SLE, supporting an autosomal recessive inheritance pattern (PMID:30008451, PMID:38469558). These investigations demonstrate that loss-of-function mutations in C1S lead to deficient complement activity and impaired clearance of apoptotic cells, a mechanism that predisposes affected individuals to autoimmunity.

In one seminal study involving 7 unrelated early-onset SLE probands, a homozygous missense alteration in C1S was identified, along with additional variants in complement genes. The segregation analysis within these families further reinforced the pathogenic role of C1S mutations, confirming that the altered gene product disrupts normal complement function (PMID:30008451). Similar findings in a separate case report described a compound heterozygote with two truncating variants, resulting in complete C1s deficiency and a classical SLE phenotype (PMID:38469558).

Genetic evidence for the association is bolstered by data from multi-patient studies that have identified ultra-rare heterozygous variants in C1S among patients with SLE, suggesting that even single-allele disruptions might contribute to the overall genetic risk in a complex inheritance background (PMID:30707351). The curated variant spectrum includes coding changes such as the reported alteration, which highlights the direct impact of C1S mutations on protein structure and function.

A representative variant from the reported cases is c.1945G>C (p.Ala649Pro). This variant, identified in a patient with early-onset SLE, exemplifies the pathogenic changes that can compromise C1s activity, thereby reducing classical complement pathway efficiency and facilitating the persistence of autoreactive immune complexes (PMID:30008451). The recurrence of such variants across unrelated families provides robust genetic evidence for the C1S-SLE association.

Functional studies support these genetic findings by demonstrating that C1s deficiency correlates with markedly reduced CH50 activity and failure of appropriate C4 cleavage. These experiments elucidate that inadequate complement activation leads to defective clearance of apoptotic bodies, which is a key contributor to SLE pathogenesis. The experimental data thus corroborate the clinical observations and highlight the mechanistic basis by which C1S mutations drive autoimmunity (PMID:38469558, PMID:11390518).

In summary, the cumulative evidence from comprehensive genetic screening, familial segregation studies, and functional assays converges to establish a strong association between pathogenic variants in C1S and the development of systemic lupus erythematosus. The integration of these findings provides a compelling basis for incorporating C1S mutational analysis into the diagnostic evaluation of early-onset SLE, thereby enhancing personalized therapeutic strategies and risk assessment in clinical practice.

Key Take‑home: Mutations in C1S are a critical driver of SLE pathogenesis, and their detection is fundamental for precise diagnosis and tailored management of affected patients.

References

• The Journal of rheumatology • 2018 • Whole Exome Sequencing in Early-onset Systemic Lupus Erythematosus PMID:30008451
• Human genetics • 2019 • Whole-genome sequencing identifies complex contributions to genetic risk by variants in genes causing monogenic systemic lupus erythematosus PMID:30707351
• Frontiers in immunology • 2023 • Complement C1s deficiency in a male Caucasian patient with systemic lupus erythematosus: a case report PMID:38469558

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