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Link to original content: https://omim.org/entry/246300
ORPHA: 548;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 4q31.3 | {Leprosy, susceptibility to} | 246300 | Autosomal dominant | 3 | TLR2 | 603028 |
A number sign (#) is used with this entry because this form of susceptibility to leprosy (LPRS3) is associated with a polymorphism in the TLR2 gene (603028) on chromosome 4q32.
See 609888 for a discussion of leprosy susceptibility in general and information on genetic heterogeneity.
LPRS3 is associated with a polymorphism in the TLR2 gene, which Rock et al. (1998) mapped to chromosome 4q32.
Kang and Chae (2001) identified an arg677-to-trp polymorphism (R677W; 603028.0001) in the intracellular domain of TLR2 in 10 (22%) of 45 Korean lepromatous leprosy patients, but not in any of 41 Korean tuberculoid patients or 45 Korean controls. They concluded that the R677W polymorphism in TLR2 has a role in susceptibility to lepromatous leprosy.
Bochud et al. (2003) found that wildtype TLR2 mediated CD14 (158120)-enhanced Mycobacterium leprae-dependent activation of NFKB (see 164011), but TLR2 containing R677W did not. They concluded that the impaired function of the R677W variant provides a molecular mechanism for the poor cellular immune response associated with lepromatous leprosy.
Malhotra et al. (2005) used a case control study to investigate whether the R677W SNP in TLR2 reported by Kang and Chae (2001) was associated with leprosy susceptibility in 286 Indian leprosy patients and 183 ethnically matched controls. Genotyping results after direct PCR sequencing led Malhotra et al. (2005) to conclude that the R677W polymorphism is not a true polymorphism of TLR2, but rather resulted from variation present in a duplicated region 23 kb upstream of TLR2 that shares 93% identity with TLR2 exon 3. Malhotra et al. (2005) also failed to detect variation in the TLR2 promoter region.
Mikita et al. (2009) investigated the R677W polymorphism in 99 Japanese leprosy patients, whose genetic background is close to that of the Korean patients studied by Kang and Chae (2001). They found that R677W was undetectable in the Japanese patients, similar to the findings in Indian patients reported by Malhotra et al. (2005). Moreover, they failed to detect any of 7 additional nonsynonymous SNPs in the TLR2 gene in the Japanese patients.
Bochud et al. (2008) analyzed 3 TLR2 polymorphisms for associations with risk of developing leprosy, leprosy type, or leprosy reactions in 441 patients and 187 controls belonging to 3 Ethiopian ethnic groups. They found that a synonymous 597C-T SNP was associated with reduced susceptibility to reversal reaction (OR of 0.34), whereas patients homozygous for a 280-bp microsatellite marker had an increased risk of reversal reaction (OR of 5.83).
Bochud, P.-Y., Hawn, T. R., Aderem, A. Cutting edge: a Toll-like receptor 2 polymorphism that is associated with lepromatous leprosy is unable to mediate mycobacterial signaling. J. Immun. 170: 3451-3454, 2003. [PubMed: 12646604] [Full Text: https://doi.org/10.4049/jimmunol.170.7.3451]
Bochud, P.-Y., Hawn, T. R., Siddiqui, M. R., Saunderson, P., Britton, S., Abraham, I., Argaw, A. T., Janer, M., Zhao, L. P., Kaplan, G., Aderem, A. Toll-like receptor 2 (TLR2) polymorphisms are associated with reversal reaction in leprosy. J. Infect. Dis. 197: 253-261, 2008. [PubMed: 18177245] [Full Text: https://doi.org/10.1086/524688]
Kang, T.-J., Chae, G.-T. Detection of Toll-like receptor 2 (TLR2) mutation in the lepromatous leprosy patients. FEMS Immun. Med. Microbiol. 31: 53-58, 2001. [PubMed: 11476982] [Full Text: https://doi.org/10.1111/j.1574-695X.2001.tb01586.x]
Malhotra, D., Relhan, V., Reddy, B. S. N., Bamezai, R. TLR2 Arg677Trp polymorphism in leprosy: revisited. Hum. Genet. 116: 413-415, 2005. [PubMed: 15726416] [Full Text: https://doi.org/10.1007/s00439-004-1249-9]
Mikita, N., Kanazawa, N., Ozaki, M., Kosaka, M., Ishii, N., Nishimura, H., Furukawa, F. No involvement of non-synonymous TLR2 polymorphisms in Japanese leprosy patients. (Letter) J. Derm. Sci. 54: 48-49, 2009. [PubMed: 19111445] [Full Text: https://doi.org/10.1016/j.jdermsci.2008.11.001]
Rock, F. L., Hardiman, G., Timans, J. C., Kastelein, R. A., Bazan, J. F. A family of human receptors structurally related to Drosophila Toll. Proc. Nat. Acad. Sci. 95: 588-593, 1998. [PubMed: 9435236] [Full Text: https://doi.org/10.1073/pnas.95.2.588]