Genetic and structural analysis of MBL2 and MASP2 polymorphisms in south‐eastern African children

Abstract

The mannose-binding lectin (MBL) pathway of complement system is activated when carbohydrate-bound MBL forms complexes with different serine proteases (MASP-1, MASP-2 and MASP-3), among which MASP-2 has a predominant functional role. Polymorphisms impairing the quantity and/or the functional activity of proteins encoded by the MBL2 and MASP2 genes have been reported in all human populations showing different allelic frequency and distribution. This likely reflects the existence of environmental influences on MBL2 and MASP2 genetic evolution. Herewith, we conducted a study in a children population from Mozambique to analyse the genetic diversity of sequences corresponding to the promoter and collagen-like region (exon 1) of MBL2 and to the CUB-1 and epidermal growth factor domain (exon 3) of MASP2, which are critical regions for the formation of functional MBL/MASP-2 complexes. Our results show a high prevalence of MBL-intermediate/low genotypes (43.5%); the description of new alleles and a high level of sequence polymorphism at both MBL2 and MASP2, with no statistical evidence for positive or balancing selection. Furthermore, Biacore analyses performed to explore the functional relevance of the MASP2 variants found [T73M (2.9%), R84Q (12.7%) and P111L (25.4%)] were compared with those of two previously reported variants (R103C and D105G). None of the analysed MASP2 variants, with the exception of D105G, interfered with interactions with either MBL or ficolins (H and L).

Genotypes Coding for Low Serum Levels of Mannose-Binding Lectin Are Underrepresented among Individuals Suffering from Noninfectious Systemic Inflammatory Response Syndrome

“…No significant differences in the frequency for the heterozygous MASP2 Asp105Gly were seen between ICU patients with SIRS and the healthy controls, the prevalence of which was in turn similar to that found in previous studies (10,48). One Caucasian patient carried the MASP2 Pro111Leu SNP, as primarily described by Lozano et al in North African individuals, which is not capable of causing reductions in the serum levels or activity of the MASP-2 (31,52). Previous studies have demonstrated a high prevalence of MBL2-deficient genotypes among patients with sepsis admitted to ICU (17,19,50).…”

“…Patients heterozygous for the MASP2 Asp 105Gly SNP have no impairment in the lectin complement pathway (10,11,51). Several additional variants have been identified in exon 3 of the MASP2 gene that do not cause a reduction of the levels or activity of the protein (31,52).…”

Leprosy Association with Low MASP-2 Levels Generated by MASP2 Haplotypes and Polymorphisms Flanking MAp19 Exon 5

“…Importantly, the distribution of p.120G did not differ between patients and controls, as well as between lepromatous and non-lepromatous patients. One might argue that, beside functional differences, the contrasting results between p.439H and p.120G could be the result of population substructure, since p.439H are most probably of African, and p.120G of European origin [9]–[11]. Nevertheless the association of the *1C2-l haplotype (harboring both p.126L and p.439H ) with leprosy per se was especially evident after the exclusion of Afro-Brazilian patients, which present at least 40% of sub-Saharan African admixture [23], [24], whereas the frequencies of p.120G in patients and controls remained similar.…”

“…MAp19 has four exclusive C-terminal amino acids, whereas MASP-2 further presents a second CUB domain, two CCP (complement control protein) domains and a serine protease domain [6]. Single nucleotide polymorphisms (SNPs) located in the exons for the CUB1, EGF and serine protease domain have been shown to modify MASP-2 functions [8]–[11]. Other polymorphisms occurring in intron 9 and in exon 10 (encoding the last CCP) were associated with different MASP-2 and MAp19 levels [9], [12], [13] (Figure 1).…”

Multiplex sequence-specific polymerase chain reaction reveals new MASP2 haplotypes associated with MASP-2 and MAp19 serum levels

“…Furthermore, MASP-2 levels have been demonstrated to be stable over time in healthy individuals [28] and vary about 100-fold in the normal Danish population [29], but only limited haplotype analysis has been performed [19,20]. To remedy this we developed a new haplotyping strategy based on multiplex polymerase chain reaction with sequence-specific primers (PCR-SSP) for 8 single nucleotide polymorphisms (SNPs) of the MASP2 gene.…”