Identification of novel coding mutation in C1qA gene in an African-American pedigree with lupus and C1q deficiency

Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
Lupus (Impact Factor: 2.2). 04/2012; 21(10):1113-8. DOI: 10.1177/0961203312443993
Source: PubMed


Homozygous C1q deficiency is an extremely rare condition and strongly associated with systemic lupus erythematosus. To assess and characterize C1q deficiency in an African-American lupus pedigree, C1q genomic region was evaluated in the lupus cases and family members.
Genomic DNA from patient was obtained and C1q A, B and C gene cluster was sequenced using next generation sequencing method. The identified mutation was further confirmed by direct Sanger sequencing method in the patient and all blood relatives. C1q levels in serum were measured using sandwich ELISA method.
In an African-American patient with lupus and C1q deficiency, we identified and confirmed a novel homozygote start codon mutation in C1qA gene that changes amino acid methionine to arginine at position 1. The Met1Arg mutation prevents protein translation (Met1Arg). Mutation analyses of the patient's family members also revealed the Met1Arg homozygote mutation in her deceased brother who also had lupus with absence of total complement activity consistent with a recessive pattern of inheritance.
The identification of new mutation in C1qA gene that disrupts the start codon (ATG to AGG (Met1Arg)) has not been reported previously and it expands the knowledge and importance of the C1q gene in the pathogenesis of lupus especially in the high-risk African-American population.

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    • "Bone marrow transplantation is a potential cure, but it has not yet been performed in humans [24,25]. Some reports show that the infusion of FFP restores C1q levels, temporarily complements hemolytic activity, and suppresses SLE symptoms for a long period [8,24]. It is therefore a valid therapy for C1q deficiency patients. "
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    ABSTRACT: C1q deficiency is a rare disease that is associated with a high probability of developing systemic lupus erythematosus. We report a 4-year-old Japanese girl who presented with fever, facial erythema, joint pain, and oral ulceration. Complement deficiencies were suspected because of her persistent hypocomplementemia and normal levels of the complement proteins C3 and C4. We identified a novel homozygous splicing mutation in the C1qB gene, c.187 + 1G > T, which is the first mutation to be confirmed in a Japanese individual. Because treatment with steroids and immunosuppressive drugs was not effective, we commenced use of fresh frozen plasma to provide C1q supplements. Currently, the patient remains almost asymptomatic, and we are attempting to control the drug dosage and administration intervals of fresh frozen plasma.
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    • "form produces no C1q, and the other form produces a dysfunctional C1q (includes non-sense and mis-sense mutations) (Kirschfink et al. 1993; Petry et al. 1997; Hoekzema et al. 1985). Genetic analysis of the C1q-deficient patients has revealed mutations affecting each of its three chains (Petry et al. 1995; Mayilyan 2012; Namjou et al. 2012; Topaloglu et al. 2012). C1q deficiency, a rare autosomal recessive disorder, is known to result in an increased risk for bacterial infections, recurrent skin lesions, chronic infections, and autoimmune diseases such as, systemic lupus erythematosus (SLE) or SLE-like diseases and lupus nephritis (Petry 1998; Bowness et al. 1994; Carroll 1998; Tsao 1998; Stone et al. 2000; Pickering et al. 2000). "
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    ABSTRACT: Complement C1q subcomponent subunit A (C1qA) is one of the three components of C1q molecule. Functional C1q is composed of eighteen polypeptide chains: six C1qA chains, six C1qB chains, and six C1qC chains, which are arranged as six heterotrimers of ABC: (ABC)6. Each of the individual C1q polypeptide chain consists of a N-terminal region and a C-terminal globular region (gC1q), of ~135 residues. Each N-terminal consists of 2-11 amino acid segments containing a half-cysteine residue that is involved in formation of inter-chain disulphide bonds, followed by a collagen-like region (CLR) consisting of ~81 residues. The collagen-like regions in A, B and C chains of each heterotrimer come together to form a triple helical collagen like structure. Further, A and B chains in each heterotrimer are bound by a disulphide bond, while C chain forms a disulphide bond with a C chain from the adjoining heterotrimer. Therefore the eighteen subunits come together to form six globular heads (gC1q), which are clusters of 3 independently folded C-terminal domains of the A, B and C chain. These globular domains recognize an array of self, non-self and altered-self ligands. C1q associates with the proenzymes C1r and C1s (2 molecules of each, in the molar ratio of 1:2:2 in a calcium dependent manner) to yield an active C1 complex, the first component of the serum complement system. C1r, upon binding of gC1q to an inciting stimulus, autoactivates itself and catalyzes breakage of a C1s ester bond, resulting in C1s activation and subsequent cleavage of C2 and C4 into their respective “a” and “b” fragments. Recognition of ligands by C1q molecule also defines C1q as a pattern recognition molecule (PRM). C1q recognizes distinct structures either directly on microbial structures and apoptotic cells, or indirectly after their recognition by antibodies or C-reactive protein (CRP). C1q in turn binds to multiple receptors (such as cC1qR (calreticulin), integrin α2β1 or other molecules on the surface of specific cell types of either myeloid or endothelial cell orgin) and shows regulated broad physiological functions beyond complement activation.
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