Clinical presentations and molecular basis of complement C1r deficiency in a male African–American patient with systemic lupus erythematosus

Abstract

Homozygous deficiencies of early components for complement activation are among the strongest genetic risk factors for human systemic lupus erythematosus (SLE). Eleven cases of C1r deficiency are documented but this is the first report on the molecular basis of C1r deficiency. The proband is an African-American male who developed SLE at 3 months of age. He had a discoid lupus rash and diffuse proliferative glomerulonephritis. Serum complement analysis of the patient showed zero CH50 activity, undetectable C1r, and reduced levels of C1s, but highly elevated levels of complement C4, C2, and C1-inhibitor. The coding regions of the mutant C1R gene with 11 exons located at chromosome 12p13 were polymerase chain reaction (PCR)-amplified and sequenced to completion. DNA sequencing revealed a homozygous C→T mutation at nucleotide-6392 in exon 10 of the C1R gene, resulting in a nonsense mutation from Arg-380 (R380X). The patient's clinically normal mother was heterozygous for this mutation. A sequence-specific primer (SSP) PCR coupled with StuI-restriction fragment length polymorphism (RFLP) was developed to detect the novel mutation. Screening of 209 African-American SLE patients suggested that the R380X mutation is a rare causal variant. Mutations leading to early complement component deficiencies in SLE are mostly private variants with large effects.

Brief Report: Deficiency of Complement 1r Subcomponent in Early‐Onset Systemic Lupus Erythematosus: The Role of Disease‐Modifying Alleles in a Monogenic Disease

“…This is the second report of a novel high‐penetrance mutation in C1R as the cause of monogenic and familial SLE. The C1r‐deficient patients in the present study are phenotypically similar to the previously reported patient with this C1r deficiency (see Supplementary Table 2, available on the Arthritis & Rheumatology web site at http://onlinelibrary.wiley.com/doi/10.1002/art.40158/abstract).…”

“…Biallelic loss‐of‐function mutations in C1S have been found in patients with lupus, but also in asymptomatic individuals . Thus far, a loss‐of‐function mutation causing complete C1r deficiency has been reported in only a single individual: a male patient of African American ancestry who developed symptoms at the age of 3 years .…”

Effects of Complement C4 Gene Copy Number Variations, Size Dichotomy, and C4A Deficiency on Genetic Risk and Clinical Presentation of Systemic Lupus Erythematosus in East Asian Populations

“…Human subjects with a homozygous genetic deficiency in any of the early components of the classical pathway of complement activation, including C1q, C1r, C1s, and C4 (details in Supplementary Figure 1, available on the Arthritis & Rheumatology web site at http://onlinelibrary.wiley.com/doi/10.1002/art.39589/abstract), almost always develop SLE, regardless of race, sex, or HLA haplotype . Under susceptible backgrounds, mice with genetic knockout of complement C4 or C1q will manifest lupus‐like phenotypes with high titers of antinuclear antibodies (ANAs) and anti‐dsDNA, and a high frequency of glomerulonephritis .…”

Deficiencies of the Complement System

“…67,68 Similarly a number of mutations responsible for C1r deficiency have been identified. 69 However, 7 of the first 12 patients with C1r deficiency were of Puerto Rican descent, suggesting they may be the descendants of a single individual who carried the mutation. 70…”

“…69,106 The deficiency appears to be inherited in an autosomal recessive fashion. The activity of the classical pathway was either normal or slightly below normal.…”