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Human Molecular Genetics Advance Access published online on August 22, 2005
Human Molecular Genetics, doi:10.1093/hmg/ddi318
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© The Author 2005. Published by Oxford University Press. All rights reserved
Received April 29, 2005
Revised August 11, 2005
Accepted August 11, 2005

Article

The "involution" of mannose-binding lectin

Jeanette Seyfarth 1, Peter Garred 1, and Hans O. Madsen 2*

1 Tissue Typing Laboratory-7631, Department of Clinical Immunology, Rigshospitalet, DK-2100 Copenhagen, Denmark
2 Tissue Typing Laboratory-7631, Department of Clinical Immunology, Rigshospitalet, Blegdamsvej 9, DK-2100 Copenhagen, Denmark

* To whom correspondence should be addressed.
Hans O. Madsen, E-mail: hom{at}rh.dk


  Abstract

Mannose-binding lectin (MBL) acts as a serum opsonin in innate immune defence and induce complement activation by the lectin pathway. In humans low levels of functional serum MBL are caused by the dominant action of three single nucleotide substitutions in exon 1 that disrupt the glycine-rich backbone structure of the protein. The presence of common MBL variant alleles are associated both with infectious and autoimmune diseases. Conversely, it has also been suggested that MBL variants are maintained due to selective advantages for the host. In man the MBL genetic system comprise one functional gene (MBL2) and one expressed pseudogene (MBL1P1), while the lower primate, the rhesus monkey resemble rodents with two functional MBL genes. We have investigated the molecular mechanisms behind the evolutionary loss of MBL expression from lower primates to man, including silencing of the MBL1P1 gene and the generation of MBL2 variant structural alleles and promoter polymorphisms leading to the present human MBL2 haplotypes. We present data showing that the MBL1P1 gene throughout evolution repeatedly has been hit and eventually silenced by mutations in the glycine residues of the collagen-like region. Our results indicate that the MBL1P1 gene selectively has been turned off during evolution through the same molecular mechanisms causing the MBL2 variant alleles in man, suggesting an evolutionary selection for low-producing MBL genes.


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