Mannan-binding Lectin - Structure - Genes and Polymorphisms

Genes and Polymorphisms

Human MBL2 gene is located on chromosome 10q11.2-q21. Mice have two homologous genes, but in human the first of them was lost. A low level expression of an MBL1 pseudogene 1 (MBL1P1) was detected in liver. The pseudogene encodes a truncated 51-amino acid protein that is homologous to the MBLA isoform in rodents and some primates.

Structural mutations in exon 1 of the human MBL2 gene, at codon 52 (Arg to Cys, allele D), codon 54 (Gly to Asp, allele B) and codon 57 (Gly to Glu, allele C), also independently reduce the level of functional serum MBL by disrupting the collagenous structure of the protein. Furthermore, several nucleotide substitutions in the promoter region of the MBL2 gene at position −550 (H/L polymorphism), −221 (X/Y polymorphism) and −427, −349, −336, del (−324 to −329), −70 and +4 (P/Q polymorphisms) affect the MBL serum concentration. Both the frequency of structural mutations and the promoter polymorphisms that are in strong linkage disequilibrium vary among ethnic groups resulting in seven major haplotypes: HYPA, LYQA, LYPA, LXPA, LYPB, LYQC and HYPD. Differences in the distribution of these haplotypes are the major cause of interracial variations in MBL serum levels. Both HYPA and LYQA are high-producing haplotypes, LYPA intermediate-producing haplotype and LXPA low-producing haplotype, whereas LYPB, LYQC and HYPD are defective haplotypes, which cause a severe MBL deficiency.

Both MBL2 and MBL1P1 genes has been repeatedly hit throughout evolution of primates. The latter silenced eventually by mutations in the glycine residues of the collagen-like region. It has been selectively 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.