Identification of a novel non-coding mutation in C1qB in a Dutch child with C1q deficiency associated with recurrent infections
Introduction
C1q is the recognition molecule of the classical pathway of complement activation (Daha et al., 2011). Next to its role in activation of the complement system, C1q has also been shown to bind to apoptotic and necrotic cells to facilitate their clearance (Korb and Ahearn, 1997, Nauta et al., 2002). In the absence of C1q, accumulation of apoptotic material was noted, which led to the formulation of the ‘waste disposal hypothesis’ (Trouw et al., 2008, Walport, 2001). Likewise, in the absence of C1q also immune complexes cannot be cleared effectively resulting in their accumulation. Over the recent years, more insight has been generated in the role of C1q in modulating the adaptive immune response (Fossati-Jimack et al., 2008, Baruah et al., 2009, Jiang et al., 2003). Collectively these data indicate that the absence of C1q may impact not only on clearance mechanisms for e.g. apoptotic cells and immune complexes but also on the adaptive immune responses (Santer et al., 2010). In most C1q-deficient individuals the balance is shifted toward autoimmunity and the development of Systemic Lupus Erythematosus (SLE). Complete genetic deficiency of C1q is strongly associated with development of SLE, but in some individuals the disease mainly presents with recurrent infections or, in exceptional cases, remains largely unnoticed (Schejbel et al., 2011, Vassallo et al., 2007, Walport et al., 1998).
The C1 complex is composed of 3 different proteins: one C1q molecule, two C1r molecules and two C1s molecules. C1q is the recognition molecule of the C1 complex and is composed of 18 polypeptide chains: 6 C1qA, 6 C1qB and 6 C1qC. Each chain has a collagen-like region (N-terminal region) and a globular head region. The C1qA chains associate with the C1qB chains as heterodimers. C1qC chains first will form homodimers and finally associate with the A–B heterodimers to eventually form a tulip-like structure (Petry, 1998). The genes encoding these three subunits are located on chromosome 1 within a genomic region of ∼25 kb and have an ACB orientation (Sellar et al., 1991). C1q is thought to be produced predominantly by immature dendritic cells and macrophages (Loos et al., 1989, Castellano et al., 2004). C1q production can be upregulated via IFN-γ stimulation in which the expression of the three chains is suggested to be synchronized via transcription factors PU.1 and IRF8 (Chen et al., 2011).
Nowadays around 65 cases of C1q deficiencies have been reported (Schejbel et al., 2011). These deficiencies are mostly caused by homozygous mutations in one of the chains. The most common mutation is in the A-chain caused by a nonsense mutation whereby a transition of C to T occurs in a codon for Glu-186 (Petry, 1998). Next to mutations causing C1q deficiency also several genetic variations in C1q have been associated with increased risk for developing autoimmunity (Martens et al., 2009, Trouw et al., 2013). To which extent mutations in different C1q chains affect the clinical presentation, e.g. infection versus SLE, is currently unclear.
Here we report on a non-coding homozygous mutation in an RNA splice site that leads to complete lack of expression of C1qB and hence lack of secretion of C1q.
Section snippets
Patient and controls
We have analyzed in detail one C1q-deficient Caucasian patient and studied materials obtained from both his parents as controls as well as a reference panel of 48 healthy adult controls collected in the LUMC. Informed consent was obtained from the parents and the controls in compliance with the Helsinki declaration.
Samples
Blood was collected from the patient and both parents in order to obtain serum and to isolate DNA. From the patient also PBMCs were collected using Ficoll-Paque density gradient
Patient
Here we describe a Dutch boy born from two Caucasian, healthy, non-consanguineous parents. During the first years of life he has suffered from recurrent upper airway infections. At the age of three he developed redness and swelling of the left ankle combined with fever (39 °C) after an injury. Initially a cellulitis was suspected and treated with flucloxacillin. Due to persistent complaints he was admitted to a local hospital. A subsequent skeletal scintigraphy yielded a hotspot of the distal
Discussion
C1q deficiency is a rare hereditary condition associated with a high prevalence of SLE. The combination of reduced clearance of dying cells and immune complexes and an altered balance in the adaptive immune system likely increases the chance to develop the autoimmune disease SLE (Baruah et al., 2009, Trendelenburg et al., 2004, Gullstrand et al., 2009). Globally around 65 patients have been described with a C1q deficiency (Schejbel et al., 2011). Interestingly these patients display substantial
Conflict of interest
The authors report no conflict of interest.
Acknowledgements
This work was supported by the European Union (Seventh Framework Programme integrated project Masterswitch: Health-F2-2008-223404 and IMI JU funded project BeTheCure, contract no 115142-2). This study was also supported by the national funding from the Netherlands Genomics Initiative (NGI) as part of the Netherlands Proteomics Center (NPC: II T5.1). L.T. was financially supported by a VIDI-Grant: 016.126.334 from NWO-Zon-MW. R.T. was financially supported by a VICI-Grant: 918.96.606 from
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