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Am J Hum Genet. 2011 Jun 10;88(6):689-705. doi: 10.1016/j.ajhg.2011.05.011.

Disease-causing mutations in genes of the complement system.

Author information

1
Department of Medical Microbiology and Immunology, Aarhus University, Wilhelm Meyers Allé 4, 8000 Aarhus C, DK-Denmark. Electronic address: sdegn@microbiology.au.dk.
2
Department of Medical Microbiology and Immunology, Aarhus University, Wilhelm Meyers Allé 4, 8000 Aarhus C, DK-Denmark.
3
Department of Medical Microbiology and Immunology, Aarhus University, Wilhelm Meyers Allé 4, 8000 Aarhus C, DK-Denmark. Electronic address: st@microbiology.au.dk.

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.

PMID:
21664996
PMCID:
PMC3113252
DOI:
10.1016/j.ajhg.2011.05.011
[Indexed for MEDLINE]
Free PMC Article

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