Genetic and functional analysis of common MRC1 exon 7 polymorphisms in leprosy susceptibility.
The chromosomal region 10p13 has been linked to paucibacillary leprosy in two independent studies. The MRC1 gene, encoding the human mannose receptor (MR), is located in the 10p13 region and non-synonymous SNPs in exon 7 of the gene have been suggested as leprosy susceptibility factors. We determined that G396S is the only non-synonymous exon 7-encoded polymorphism in 396 unrelated Vietnamese subjects. This SNP was genotyped in 490 simplex and 90 multiplex leprosy families comprising 704 patients (47% paucibacillary; 53% multibacillary). We observed significant under-transmission of the serine allele of the G396S polymorphism with leprosy per se (P = 0.036) and multibacillary leprosy (P = 0.034). In a sample of 384 Brazilian leprosy cases (51% paucibacillary; 49% multibacillary) and 399 healthy controls, we observed significant association of the glycine allele of the G396S polymorphism with leprosy per se (P = 0.016) and multibacillary leprosy (P = 0.023). In addition, we observed a significant association of exon 7 encoded amino acid haplotypes with leprosy per se (P = 0.012) and multibacillary leprosy (P = 0.004). Next, we tested HEK293 cells over-expressing MR constructs (293-MR) with three exon 7 haplotypes of MRC1 for their ability to bind and internalize ovalbumin and zymosan, two classical MR ligands. No difference in uptake was measured between the variants. In addition, 293-MR failed to bind and internalize viable Mycobacterium leprae and BCG. We propose that the MR-M. leprae interaction is modulated by an accessory host molecule of unknown identity.
Alter
Andrea
A
Department of Medicine, McGill Centre for the Study of Host Resistance, Research Institute of the McGill University Health Centre, McGill University, Montreal, QC, Canada.
de Léséleuc
Louis
L
Van Thuc
Nguyen
N
Thai
Vu Hong
VH
Huong
Nguyen Thu
NT
Ba
Nguyen Ngoc
NN
Cardoso
Cynthia Chester
CC
Grant
Audrey Virginia
AV
Abel
Laurent
L
Moraes
Milton Ozório
MO
Alcaïs
Alexandre
A
Schurr
Erwin
E
D016022:Case-Control Studies; D002478:Cells, Cultured; D003001:Cloning, Molecular; D005091:Exons; D020022:Genetic Predisposition to Disease; D006801:Humans; D037181:Lectins, C-Type / Q000235:genetics* / Q000378:metabolism / Q000502:physiology; D007918:Leprosy / Q000235:genetics*; D015810:Linkage Disequilibrium; D000090323:Mannose Receptor; D037241:Mannose-Binding Lectins / Q000235:genetics* / Q000378:metabolism / Q000502:physiology; D050505:Mutant Proteins / Q000235:genetics; D009163:Mycobacterium bovis / Q000378:metabolism; D009166:Mycobacterium leprae / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide / Q000502:physiology; D011485:Protein Binding; D011956:Receptors, Cell Surface / Q000235:genetics* / Q000378:metabolism / Q000502:physiology; D014162:Transfection
D037181:Lectins, C-Type; D000090323:Mannose Receptor; D037241:Mannose-Binding Lectins; D050505:Mutant Proteins; D011956:Receptors, Cell Surface