RGD Reference Report - An N-ethyl-N-nitrosourea (ENU)-induced dominant negative mutation in the JAK3 kinase protects against cerebral malaria. - Rat Genome Database

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An N-ethyl-N-nitrosourea (ENU)-induced dominant negative mutation in the JAK3 kinase protects against cerebral malaria.

Authors: Bongfen, SE  Rodrigue-Gervais, IG  Berghout, J  Torre, S  Cingolani, P  Wiltshire, SA  Leiva-Torres, GA  Letourneau, L  Sladek, R  Blanchette, M  Lathrop, M  Behr, MA  Gruenheid, S  Vidal, SM  Saleh, M  Gros, P 
Citation: Bongfen SE, etal., PLoS One. 2012;7(2):e31012. doi: 10.1371/journal.pone.0031012. Epub 2012 Feb 21.
RGD ID: 11531103
Pubmed: PMID:22363534   (View Abstract at PubMed)
PMCID: PMC3283600   (View Article at PubMed Central)
DOI: DOI:10.1371/journal.pone.0031012   (Journal Full-text)

Cerebral malaria (CM) is a lethal neurological complication of malaria. We implemented a genome-wide screen in mutagenized mice to identify host proteins involved in CM pathogenesis and whose inhibition may be of therapeutic value. One pedigree (P48) segregated a resistance trait whose CM-protective effect was fully penetrant, mapped to chromosome 8, and identified by genome sequencing as homozygosity for a mis-sense mutation (W81R) in the FERM domain of Janus-associated kinase 3 (Jak3). The causative effect of Jak3(W81R) was verified by complementation testing in Jak3(W81R/-) double heterozygotes that were fully protected against CM. Jak3(W81R) homozygotes showed defects in thymic development with depletion of CD8(+) T cell, B cell, and NK cell compartments, and defective T cell-dependent production of IFN-gamma. Adoptive transfer of normal splenocytes abrogates CM resistance in Jak3(W81R) homozygotes, an effect attributed to the CD8(+) T cells. Jak3(W81R) behaves as a dominant negative variant, with significant CM resistance of Jak3(W81R/+) heterozygotes, compared to CM-susceptible Jak3(+/+) and Jak3(+/-) controls. CM resistance in Jak3(W81R/+) heterozygotes occurs in presence of normal T, B and NK cell numbers. These findings highlight the pathological role of CD8(+) T cells and Jak3-dependent IFN-gamma-mediated Th1 responses in CM pathogenesis.

RGD Manual Disease Annotations    Click to see Annotation Detail View

Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
JAK3Humancerebral malaria  ISOJak3 (Mus musculus) RGD 
Jak3Ratcerebral malaria  ISOJak3 (Mus musculus) RGD 
Jak3Mousecerebral malaria  IMP  RGD 

Objects Annotated

Genes (Rattus norvegicus)
Jak3  (Janus kinase 3)

Genes (Mus musculus)
Jak3  (Janus kinase 3)

Genes (Homo sapiens)
JAK3  (Janus kinase 3)

Additional Information