Alternative titles; symbols
ORPHA: 1247; DO: 0050597;
Cytogenetic location: 5q31-q33 Genomic coordinates (GRCh38): 5:131,200,001-160,500,000
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 5q31-q33 | {Schistosoma mansoni infection, susceptibility/resistance to} | 181460 | Autosomal dominant | 2 |
Abel et al. (1991) reviewed evidence suggesting that for individuals having frequent contacts with waters infested with the cercaria of Schistosoma mansoni, both infection intensities and reinfection after treatment depend, in large part, on their intrinsic susceptibility/resistance to infection, suggesting a role of genetic factors. In studies on 20 Brazilian pedigrees, they found results consistent with the existence of a codominant major gene controlling human susceptibility/resistance to infection by S. mansoni. The frequency of the deleterious gene was estimated to be 0.20 to 0.25; thus, about 5% of the population was predisposed to high infection, 60% was resistant, and 35% had an intermediate, although fairly good, level of resistance.
Worldwide, 300 million individuals are said to be at risk of infection by schistosomes and around 200,000 die each year of schistosomiasis. Following up on the study of Abel et al. (1991), Marquet et al. (1996) performed a genomewide study on 142 Brazilian subjects belonging to 11 informative families to localize the susceptibility gene, referred to as SM1 by them. Their results showed linkage to 5q31-q33 with maximum 2-point lod scores of 4.74 (theta = 0.07) and 4.52 (theta = 0.04) for D5S636 and the gene for colony stimulating factor-1 receptor (CSF1R; 164770), respectively. This was corroborated by multipoint analysis, indicating a close proximity to CSF1R as the most likely location of SM1. CSF1R has been mapped to 5q33.2-q33.3. This region contained several candidate genes encoding immunologic molecules that had been shown to play important roles in human protection against schistosomes, including CSF2 (138960), IL3 (147740), IL4 (147780), IL5 (147850), IRF1 (147575), and IL13 (147683).
The conclusions from the study in Brazil (Marquet et al., 1996) in a region hyperendemic for schistosomiasis were supported by studies in a newly emerged, epidemic focus of intestinal schistosomiasis in northern Senegal (2:Muller-Myhsok et al., 1997). The Senegalese data replicated the findings indicating an SM1 locus on 5q31-q33. Differences observed between the 2 populations were thought to be attributable to the relatively short exposure (no longer than 7 years) in Senegal, different environmental factors (for instance, other infectious diseases, such as malaria, that are prevalent in the Senegalese study area but not in the Brazilian study area), and other factors.
Marquet et al. (1999) reported the full results of a genomewide search performed on the Brazilian population previously studied by Marquet et al. (1996). Although significant evidence of linkage was found only for 5q31-q33, 3 additional regions, 1p22.2, 7q36, and 21q22-qter, yielded promising, although not significant, lod score values.
The same Brazilian group that estimated that a major gene accounts for more than 50% of the variance of infection levels for S. mansoni (Abel et al., 1991) could find no evidence of linkage between susceptibility or resistance to schistosomiasis, as defined by mean fecal egg count, and HLA (Chiarella et al., 1998). Several association studies have correlated HLA with hepatosplenomegaly in schistosomiasis. Chiarella et al. (1998) concluded that if HLA plays an important role in specific immune responses to S. mansoni, it may involve the development of different clinical aspects of the disease, such as granuloma formation and development of hepatosplenomegaly.
Dessein et al. (1999) determined that infection levels and advanced hepatic fibrosis in schistosomiasis are controlled by distinct loci; see 604201.
The propensity of helminths, such as schistosomes, to immunomodulate the host's immune system is an essential aspect of their survival. Ritter et al. (2010) stimulated mouse bone marrow-derived dendritic cells (BMDCs) with soluble schistosomal egg antigens (SEAs) after prestimulation with different TLR ligands and observed suppressed secretion of Tnf (191160) and Il6 (147620) and increased Nlrp3 (606416)-dependent Il1b (147720) production. Induction of Il1b was phagocytosis-independent, but it required production of reactive oxygen species, potassium efflux, and functional Syk (600085) signaling, suggesting inflammasome activation. SEA stimulation of BMDCs lacking Fcrg (see 146740) or dectin-2 (CLEC6A; 613579) resulted in significantly reduced Il1b production compared with wildtype BMDCs, suggesting that SEA triggers dectin-2, which couples with Fcrg to activate the Syk kinase signaling pathway that controls Nlrp3 inflammasome activation and Il1b release. Infection of mice lacking Nlrp3 or the central inflammasome adaptor Asc (PYCARD; 606838) with S. mansoni resulted in no difference in parasite burden, but decreased liver pathology and downregulated Th1, Th2, and Th17 adaptive immune responses. Ritter et al. (2010) concluded that SEA components induce IL1B production and that NLRP3 plays a crucial role during S. mansoni infection.
Smith et al. (2005) identified a molecule produced by Schistosoma eggs, termed S. mansoni chemokine-binding protein (smCKBP), that bound the chemokines CCL2 (158105), CCL3 (182283), CCL5 (187011), CXCL8 (146930), and CX3CL1 (601880). SmCKBP blocked interaction of these chemokines with their receptors and thereby inhibited induction of inflammation. Smith et al. (2005) proposed that since smCKBP is unrelated to host proteins, it may have potential as an antiinflammatory agent. They concluded that smCKBP explains, at least in part, how modulation of the immune system allows the host to tolerate chronic worm infections without overt morbidity.
Abel, L., Demenais, F., Prata, A., Souza, A. E., Dessein, A. Evidence for the segregation of a major gene in human susceptibility/resistance to infection by Schistosoma mansoni. Am. J. Hum. Genet. 48: 959-970, 1991. [PubMed: 1902058]
Chiarella, J. M., Goldberg, A. C., Abel, L., Carvalho, E. M., Kalil, J., Dessein, A. Absence of linkage between MHC and a gene involved in susceptibility to human schistosomiasis. Braz. J. Med. Biol. Res. 31: 665-670, 1998. [PubMed: 9698772] [Full Text: https://doi.org/10.1590/s0100-879x1998000500010]
Dessein, A. J., Hillaire, D., Elwali, N. E. M. A., Marquet, S., Mohamed-Ali, Q., Mirghani, A., Henri, S., Abdelhameed, A. A., Saeed, O. K., Magzoub, M. M. A., Abel, L. Severe hepatic fibrosis in Schistosoma mansoni infection is controlled by a major locus that is closely linked to the interferon-gamma receptor gene. Am. J. Hum. Genet. 65: 709-721, 1999. [PubMed: 10441577] [Full Text: https://doi.org/10.1086/302526]
Marquet, S., Abel, L., Hillaire, D., Dessein, A. Full results of the genome-wide scan which localises a locus controlling the intensity of infection by Schistosoma mansoni on chromosome 5q31-q33. Europ. J. Hum. Genet. 7: 88-97, 1999. [PubMed: 10094195] [Full Text: https://doi.org/10.1038/sj.ejhg.5200243]
Marquet, S., Abel, L., Hillaire, D., Dessein, H., Kalil, J., Feingold, J., Weissenbach, J., Dessein, A. J. Genetic localization of a locus controlling the intensity of infection by Schistosoma mansoni on chromosome 5q31-q33. Nature Genet. 14: 181-184, 1996. [PubMed: 8841190] [Full Text: https://doi.org/10.1038/ng1096-181]
Muller-Myhsok, B., Stelma, F. F., Guisse-Sow, F., Muntau, B., Thye, T., Burchard, G. D., Gryseels, B., Horstmann, R. D. Further evidence suggesting the presence of a locus, on human chromosome 5q31-q33, influencing the intensity of infection with Schistosoma mansoni. (Letter) Am. J. Hum. Genet. 61: 452-454, 1997. [PubMed: 9311752] [Full Text: https://doi.org/10.1016/S0002-9297(07)64073-7]
Ritter, M., Gross, O., Kays, S., Ruland, J., Nimmerjahn, N., Saijo, S., Tschopp, J., Layland, L. E., Prazeres da Costa, C. Schistosoma mansoni triggers dectin-2, which activates the Nlrp3 inflammasome and alters adaptive immune responses. Proc. Nat. Acad. Sci. 107: 20459-20464, 2010. [PubMed: 21059925] [Full Text: https://doi.org/10.1073/pnas.1010337107]
Smith, P., Fallon, R. E., Mangan, N. E., Walsh, C. M., Saraiva, M., Sayers, J. R., McKenzie, A. N. J., Alcami, A., Fallon, P. G. Schistosoma mansoni secretes a chemokine binding protein with antiinflammatory activity. J. Exp. Med. 202: 1319-1325, 2005. [PubMed: 16301741] [Full Text: https://doi.org/10.1084/jem.20050955]