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Genetic dissection of the ity3 locus identifies a role for ncf2 co-expression modules and suggests selp as a candidate gene underlying the ity3.2 locus.

Khan RT, Chevenon M, Yuki KE, Malo D - Front Immunol (2014)

Bottom Line: Typhoid fever and salmonellosis, which are caused by Salmonella typhi and typhimurium, respectively, are responsible for significant morbidity and mortality in both developed and developing countries.In the current paper, we provided further evidence supporting a role for Ncf2 (neutrophil cytosolic factor 2 a subunit of NADPH oxidase) as the gene underlying the Ity3.1 sub-locus.Gene expression profiling indicated that the Ity3.1 sub-locus defined a global gene expression signature with networks articulated around Ncf2.

View Article: PubMed Central - PubMed

Affiliation: Department of Human Genetics, McGill University , Montreal, QC , Canada ; Complex Traits Group, McGill University , Montreal, QC , Canada.

ABSTRACT
Typhoid fever and salmonellosis, which are caused by Salmonella typhi and typhimurium, respectively, are responsible for significant morbidity and mortality in both developed and developing countries. We model typhoid fever using mice infected with Salmonella typhimurium, which results in a systemic disease, whereby the outcome of infection is variable in different inbred strains of mice. This model recapitulates several clinical aspects of the human disease and allows the study of the host response to Salmonella typhimurium infection in vivo. Previous work in our laboratory has identified three loci (Ity, Ity2, and Ity3) in the wild-derived MOLF/Ei mice influencing survival after infection with Salmonella typhimurium. Fine mapping of the Ity3 locus indicated that two sub-loci contribute collectively to the susceptibility of B6.MOLF-Ity/Ity3 congenic mice to Salmonella infection. In the current paper, we provided further evidence supporting a role for Ncf2 (neutrophil cytosolic factor 2 a subunit of NADPH oxidase) as the gene underlying the Ity3.1 sub-locus. Gene expression profiling indicated that the Ity3.1 sub-locus defined a global gene expression signature with networks articulated around Ncf2. Furthermore, based on differential expression and complementation analysis using Selp (selectin-P) knock-out mice, Selp was identified as a strong candidate gene for the Ity3.2 sub-locus.

No MeSH data available.


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Genes under the influence of Ity3.2. List of genes showing a similar expression pattern in Ity3 and Ity3.RecN, and different from Ity and Ity3.RecG. Ints7 (integrator complex subunit 7), F5 (coagulation factor V), Pbx1 (pre B cell leukemia homeobox 1), Cacybp (calcyclin binding protein), Nenf (neuron derived neurotrophic factor), Angel2 [angel homolog 2 (Drosophila)], Cox6a2 (cytochrome c oxidase subunit VIa polypeptide 2), Selp (selectin, platelet), Vamp4 (vesicle-associated membrane protein 4), Sccpdh [saccharopine dehydrogenase (putative)], Ctsw (cathepsin W), Fh1 (fumarate hydratase 1).
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Figure 5: Genes under the influence of Ity3.2. List of genes showing a similar expression pattern in Ity3 and Ity3.RecN, and different from Ity and Ity3.RecG. Ints7 (integrator complex subunit 7), F5 (coagulation factor V), Pbx1 (pre B cell leukemia homeobox 1), Cacybp (calcyclin binding protein), Nenf (neuron derived neurotrophic factor), Angel2 [angel homolog 2 (Drosophila)], Cox6a2 (cytochrome c oxidase subunit VIa polypeptide 2), Selp (selectin, platelet), Vamp4 (vesicle-associated membrane protein 4), Sccpdh [saccharopine dehydrogenase (putative)], Ctsw (cathepsin W), Fh1 (fumarate hydratase 1).

Mentions: We next studied genes showing a similar regulation pattern in Ity3 and Ity3.RecN to understand the pathways differentially regulated in Ity3.2 and identify potential candidate genes for the Ity3.2 locus. There were only 14 genes that showed a similar expression pattern in Ity3 and RecN (Figure 5). Of these 14 genes, 12 are located on chromosome 1 and 6 genes (F5, Pbx1, Cacybp, Bc055342, Selp, and Vamp4) lie within the genomic region harboring Ity3.2 (Table 1). Sequence variations have been reported between the MOLF/Ei and C57BL/6J in coagulation factor F5, the cDNA BC055324 and selectin P (Selp). The coagulation factor V is synthesized by the liver and is involved in the acceleration of prothrombin to thrombin conversion (32). Coagulation Factor V deficiency leads to a bleeding disorder associated with mild to severe hemorrhagic symptoms (33). The cDNA BC055324 is poorly characterized and its function is not known. The Selp gene encodes for an adhesion molecule that mediates the recruitment of immune cells to the site of inflammation and is critical for the host immune response to infection making this gene an attractive candidate gene for Ity3.2.


Genetic dissection of the ity3 locus identifies a role for ncf2 co-expression modules and suggests selp as a candidate gene underlying the ity3.2 locus.

Khan RT, Chevenon M, Yuki KE, Malo D - Front Immunol (2014)

Genes under the influence of Ity3.2. List of genes showing a similar expression pattern in Ity3 and Ity3.RecN, and different from Ity and Ity3.RecG. Ints7 (integrator complex subunit 7), F5 (coagulation factor V), Pbx1 (pre B cell leukemia homeobox 1), Cacybp (calcyclin binding protein), Nenf (neuron derived neurotrophic factor), Angel2 [angel homolog 2 (Drosophila)], Cox6a2 (cytochrome c oxidase subunit VIa polypeptide 2), Selp (selectin, platelet), Vamp4 (vesicle-associated membrane protein 4), Sccpdh [saccharopine dehydrogenase (putative)], Ctsw (cathepsin W), Fh1 (fumarate hydratase 1).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4129629&req=5

Figure 5: Genes under the influence of Ity3.2. List of genes showing a similar expression pattern in Ity3 and Ity3.RecN, and different from Ity and Ity3.RecG. Ints7 (integrator complex subunit 7), F5 (coagulation factor V), Pbx1 (pre B cell leukemia homeobox 1), Cacybp (calcyclin binding protein), Nenf (neuron derived neurotrophic factor), Angel2 [angel homolog 2 (Drosophila)], Cox6a2 (cytochrome c oxidase subunit VIa polypeptide 2), Selp (selectin, platelet), Vamp4 (vesicle-associated membrane protein 4), Sccpdh [saccharopine dehydrogenase (putative)], Ctsw (cathepsin W), Fh1 (fumarate hydratase 1).
Mentions: We next studied genes showing a similar regulation pattern in Ity3 and Ity3.RecN to understand the pathways differentially regulated in Ity3.2 and identify potential candidate genes for the Ity3.2 locus. There were only 14 genes that showed a similar expression pattern in Ity3 and RecN (Figure 5). Of these 14 genes, 12 are located on chromosome 1 and 6 genes (F5, Pbx1, Cacybp, Bc055342, Selp, and Vamp4) lie within the genomic region harboring Ity3.2 (Table 1). Sequence variations have been reported between the MOLF/Ei and C57BL/6J in coagulation factor F5, the cDNA BC055324 and selectin P (Selp). The coagulation factor V is synthesized by the liver and is involved in the acceleration of prothrombin to thrombin conversion (32). Coagulation Factor V deficiency leads to a bleeding disorder associated with mild to severe hemorrhagic symptoms (33). The cDNA BC055324 is poorly characterized and its function is not known. The Selp gene encodes for an adhesion molecule that mediates the recruitment of immune cells to the site of inflammation and is critical for the host immune response to infection making this gene an attractive candidate gene for Ity3.2.

Bottom Line: Typhoid fever and salmonellosis, which are caused by Salmonella typhi and typhimurium, respectively, are responsible for significant morbidity and mortality in both developed and developing countries.In the current paper, we provided further evidence supporting a role for Ncf2 (neutrophil cytosolic factor 2 a subunit of NADPH oxidase) as the gene underlying the Ity3.1 sub-locus.Gene expression profiling indicated that the Ity3.1 sub-locus defined a global gene expression signature with networks articulated around Ncf2.

View Article: PubMed Central - PubMed

Affiliation: Department of Human Genetics, McGill University , Montreal, QC , Canada ; Complex Traits Group, McGill University , Montreal, QC , Canada.

ABSTRACT
Typhoid fever and salmonellosis, which are caused by Salmonella typhi and typhimurium, respectively, are responsible for significant morbidity and mortality in both developed and developing countries. We model typhoid fever using mice infected with Salmonella typhimurium, which results in a systemic disease, whereby the outcome of infection is variable in different inbred strains of mice. This model recapitulates several clinical aspects of the human disease and allows the study of the host response to Salmonella typhimurium infection in vivo. Previous work in our laboratory has identified three loci (Ity, Ity2, and Ity3) in the wild-derived MOLF/Ei mice influencing survival after infection with Salmonella typhimurium. Fine mapping of the Ity3 locus indicated that two sub-loci contribute collectively to the susceptibility of B6.MOLF-Ity/Ity3 congenic mice to Salmonella infection. In the current paper, we provided further evidence supporting a role for Ncf2 (neutrophil cytosolic factor 2 a subunit of NADPH oxidase) as the gene underlying the Ity3.1 sub-locus. Gene expression profiling indicated that the Ity3.1 sub-locus defined a global gene expression signature with networks articulated around Ncf2. Furthermore, based on differential expression and complementation analysis using Selp (selectin-P) knock-out mice, Selp was identified as a strong candidate gene for the Ity3.2 sub-locus.

No MeSH data available.


Related in: MedlinePlus