C1q Deficiency

A number sign (#) is used with this entry because C1q deficiency can be caused by homozygous mutation in the C1QA (120550), C1QB (120570), or C1QC (120575) gene, all of which are located on chromosome 1p36.

Description

C1q deficiency is a rare autosomal recessive disorder characterized by recurrent skin lesions, chronic infections, and an increased risk of autoimmune diseases, particularly systemic lupus erythematosus (SLE; see 152700) or SLE-like diseases. It has also been associated with chronic glomerulonephritis and renal failure. C1q deficiency presents in 2 different forms, absent C1q protein or presence of a dysfunctional molecule (summary by Topaloglu et al., 1996 and Vassallo et al., 2007).

Clinical Features

Thompson et al. (1980) reported C1q deficiency in a 4-year-old son of first-cousin Pakistani parents, who presented with a lupus-like illness and later developed glomerulonephritis. A younger sister, as yet clinically unaffected, had the same complement profile and a younger brother had half-normal functional C1 levels. The heterozygous status of both parents, the younger brother, and an older sister was suggested by the presence of double lines on immunochemical analysis of serum from these persons using anti-C1q antiserum; one line showed a reaction of identity with the abnormal C1q of the proband, whereas the other showed a reaction of identity with normal C1q.

Mampaso et al. (1981) described 2 brothers and a sister from the Canary Islands, Spain, who presented with a cutaneous disorder manifest as vesicles, hyperpigmentation, and atrophic areas that were exacerbated upon light exposure. All 3 sibs had capsular posterior cataracts. One patient had loss of eyelashes, eyebrows, and scalp hair. The patients also had hematuria, but laboratory studies showed normal renal function. Renal biopsies showed mesangial proliferative glomerulonephritis in all patients, tubulointerstitial abnormalities in 2, and deposition of immune complexes in all. Serum analysis showed complete lack of serum C1q and the presence of various autoantibodies, consistent with an autoimmune disorder.

Hannema et al. (1984) found deficiency of C1q in 2 sisters and a brother. In these persons a dysfunctional C1q molecule was characterized by low molecular weight and antigenic deficiency. In the 2 sisters a systemic lupus erythematosus-like disease began at ages 20 and 23, respectively, resulting in death of 1 of them. All 3 sibs suffered from glomerulonephritis during childhood. The brother was apparently healthy but showed membranous glomerulopathy, stage 1, on renal biopsy.

Topaloglu et al. (1996) described 2 sibs with C1q deficiency. Both presented with a photosensitive rash, and during follow-up 1 developed SLE with proteinuria in the nephrotic range. The other sib had microscopic hematuria with a history of macroscopic hematuria. Renal biopsies revealed mesangioproliferative glomerulonephritis in 1 and IgA nephropathy in the other. Antibody response to hepatitis B vaccine was normal in affected and unaffected members of the family.

Topaloglu et al. (1996) stated that of the 34 reported patients with C1q deficiency, all but one had SLE or an SLE-like illness.

Marquart et al. (2007) described 3 affected sisters from an Inuit family with C1Q deficiency. All 3 had lupus-like skin involvement and 2 had episodes of pneumonia and septicemia; none had renal involvement.

Schejbel et al. (2011) reported a 10-year-old boy from Kosova with C1q deficiency who had SLE. His initial symptoms were malar rach, discoid rash, and oral ulceration. They also described 2 Sudanese sibs, aged 4 and 10 years, with C1q deficiency with SLE, whose initial symptoms were cutaneous lupus, bacterial meningitis, and in 1 brother bacterial keratitis. Neither had signs of renal involvement.

Higuchi et al. (2013) reported a 4-year-old Japanese girl with C1q deficiency who had a 3-month history of fever, facial erythema, joint pain, and oral ulceration. She had been diagnosed with discoid lupus erythematosus. Total complement activity (CH50) was not detectable, but C3 and C4 levels were normal.

Reviews

Rother (1986) gave a summary of reported deficiencies of components of complement. Many examples of deficiencies of C1q were listed, most of them associated with systemic lupus erythematosus or glomerulonephritis.

Molecular Genetics

Mutations in the C1QB Gene

The first molecular lesion in C1q deficiency was reported by McAdam et al. (1988): a homozygous 455G-A transition in the C1QB gene (120570.0001), resulting in a premature stop codon at amino acid 150.

In a 4-year-old Japanese girl with C1Q deficiency, Higuchi et al. (2013) identified homozygosity for a splice site mutation (c.187+1G-T; 120570.0002) in the C1QB gene. A sib under the age of 1 year was also homozygous for the mutation, whereas her parents and a sib were heterozygous.

In 3 affected sisters from an Inuit family segregating C1Q deficiency, Marquart et al. (2007) identified homozygosity for a missense mutation (G217R; 120570.0003) in the C1QB gene. The mutation segregated with the deficiency in the family.

Mutations in the C1QA Gene

In 2 sibs with C1q deficiency, Topaloglu et al. (1996) identified homozygosity for a C-T transition in codon 186 of the C1QA gene (120550.0001) that resulted in a gln-to-stop (Q186X) substitution. The mutation was present in heterozygous state in both parents and in 2 unaffected sibs. Topaloglu et al. (1996) stated that the same mutation had been described in an affected member of a Slovakian family with C1q deficiency by Petry et al. (1995).

Petry et al. (1997) identified homozygosity for the Q186X mutation in affected members of 3 Turkish families. In 1 family, an asymptomatic sister of the proband was also found to be homozygous for the mutation. Petry et al. (1997) hypothesized that this defective allele is present in the population of southeast Europe and Turkey.

In 2 Sudanese sibs with C1q deficiency, Schejbel et al. (2011) identified a homozygous truncating mutation in the C1QA gene (W194X; 120550.0002).

Mutations in the C1QC Gene

In patients with C1q deficiency, Slingsby et al. (1996) identified homozygous mutations in the C1QC gene (120575.0001-120575.0003).

In a 10-year-old boy with C1QC deficiency, Schejbel et al. (2011) identified one of the same mutations (R41X; 120575.0002) reported by Slingsby et al. (1996).

In an affected 40-year-old man from a Spanish family segregating C1Q deficiency, previously described by Mampaso et al. (1981), Lopez-Lera et al. (2014) identified homozygosity for a missense mutation (G164S; 120575.0004) in the C1QC gene.

Animal Model

The complement system plays a paradoxical role in development and expression of autoimmunity in humans. The activation of complement in SLE contributes to tissue injury. In contrast, inherited deficiency of classic pathway components, particularly C1q, is probably associated with development of SLE. This leads to the hypothesis that a physiologic action of the early part of the classic pathway protects against development of SLE and implies that C1q may play a key role in this respect. Botto et al. (1998) generated C1q-deficient (C1qa -/-) mice by gene targeting and monitored them for 8 months. C1qa -/- mice had increased mortality and higher titers of autoantibodies, compared with strain-matched controls. Of the C1qa -/- mice, 25% had glomerulonephritis with immune deposits and multiple apoptotic cell bodies. Among mice without glomerulonephritis, there were significantly greater numbers of glomerular apoptotic bodies in, C1y-deficient mice compared with controls. The phenotype associated with C1q deficiency was modified by background genes. These findings are compatible with the hypothesis that C1q deficiency causes autoimmunity by impairment of the clearance of apoptotic cells.

Garlanda et al. (2002) found that C1q-deficient mice were highly susceptible to invasive pulmonary aspergillus infection, which could be reversed by administration of pentraxin-3 (PTX3; 602492).

Deficiency of C1q, the initiator of the complement classical pathway, is associated with the development of SLE. Ling et al. (2018) used a mouse model of SLE to demonstrate that C1q, but not C3 (120700), restrains the response to self-antigens by modulating the mitochondrial metabolism of CD8 (186910)+ T cells, which can themselves propagate autoimmunity. C1q deficiency also triggers an exuberant effector CD8+ T cell response to chronic viral infection, leading to lethal immunopathology. Ling et al. (2018) concluded that these data established a link between C1q and CD8+ T cell metabolism and may explain how C1q protects against lupus, with implications for the role of viral infections in the perpetuation of autoimmunity.