Disease-Causing Mutations in Genes of the Complement System

Abstract

Recent studies have revealed profound developmental consequences of mutations in genes encoding proteins of the lectin pathway of complement activation, a central component of the innate immune system. Apart from impairment of immunity against microorganisms, it is known that hereditary deficiencies of this system predispose one to autoimmune conditions. Polymorphisms in complement genes are linked to, for example, atypical hemolytic uremia and age-dependent macular degeneration. The complement system comprises three convergent pathways of activation: the classical, the alternative, and the lectin pathway. The recently discovered lectin pathway is less studied, but polymorphisms in the plasma pattern-recognition molecule mannan-binding lectin (MBL) are known to impact its level, and polymorphisms in the MBL-associated serine protease-2 (MASP-2) result in defects of complement activation. Recent studies have described roles outside complement and immunity of another MBL-associated serine protease, MASP-3, in the etiology of 3MC syndrome, an autosomal-recessive disorder involving a spectrum of developmental features, including characteristic facial dysmorphism. Syndrome-causing mutations were identified in MASP1, encoding MASP-3 and two additional proteins, MASP-1 and MAp44. Furthermore, an association was discovered between 3MC syndrome and mutations in COLEC11, encoding CL-K1, another molecule of the lectin pathway. The findings were confirmed in zebrafish, indicating that MASP-3 and CL-K1 underlie an evolutionarily conserved pathway of embryonic development. Along with the discovery of a role of C1q in pruning synapses in mice, these recent advances point toward a broader role of complement in development. Here, we compare the functional immunologic consequences of "conventional" complement deficiencies with these newly described developmental roles.

Complement genetics, deficiencies, and disease associations

“…A patient who was homozygous for this mutation had recurrent infections (Munthe-Fog et al, 2009). Along with MASP1 (MASP-1/3 and MAp44 proteins) and MASP2 (MASP-2 and MAp19 proteins), a number of SNPs have been described for FCNs (Garred et al, 2010;Degn et al, 2011). However, the importance of ficolins in general and the genetic variations in FCN genes in particular remain largely unknown.…”

Lectin pathway of complement activation and relation with clinical complications in critically ill children

“…The MASP1 gene encodes a transcript that may be spliced to form mRNAs encoding the three proteins MASP-1, MASP-3, and MAp-44. MASP-1 and MASP-3 share five structural domains but differ by having two different serine protease domains (28). MAp-44 shares the first four structural domains with MASP-1 and MASP-3 but has in addition a unique 17 amino acid C-terminal end.…”

“…Recombinant MASP-3 has some activity on insulin-like growth factor-binding protein-5 and some synthetic substrates (27). A critical role of MASP-3 in insulin-like growth factor-binding protein-5 availability during craniofacial, muscle, and neural crest development was suggested based on specific mutations (28)(29)(30). In mice, MASP-1 and MASP-3 play a role in the alternative pathway of complement activation and thus might act as a backup system when the lectin pathway is deficient (31).…”

Mannan-Binding Lectin-Associated Serine Protease (MASP)-1 Is Crucial for Lectin Pathway Activation in Human Serum, whereas neither MASP-1 nor MASP-3 Is Required for Alternative Pathway Function

“…Clinically, absence or dysfunctionality of complement components may lead to either susceptibility to infections or autoinflammatory reactions due to hyperactivation, for example, systemic lupus erythematosus-like syndrome or hemolytic uremic syndrome (8).…”