Jinx, an MCMV susceptibility phenotype caused by disruption of Unc13d: a mouse model of type 3 familial hemophagocytic lymphohistiocytosis.
Mouse cytomegalovirus (MCMV) susceptibility often results from defects of natural killer (NK) cell function. Here we describe Jinx, an N-ethyl-N-nitrosourea-induced MCMV susceptibility mutation that permits unchecked proliferation of the virus, causing death. In Jinx homozygotes, activated NK cells and cytotoxic T lymphocytes (CTLs) fail to degranulate, although they retain the ability to produce cytokines, and cytokine levels are markedly elevated in the blood of infected mutant mice. Jinx was mapped to mouse chromosome 11 on a total of 246 meioses and confined to a 4.60-million basepair critical region encompassing 122 annotated genes. The phenotype was ascribed to the creation of a novel donor splice site in Unc13d, the mouse orthologue of human MUNC13-4, in which mutations cause type 3 familial hemophagocytic lymphohistiocytosis (FHL3), a fatal disease marked by massive hepatosplenomegaly, anemia, and thrombocytopenia. Jinx mice do not spontaneously develop clinical features of hemophagocytic lymphohistiocytosis (HLH), but do so when infected with lymphocytic choriomeningitis virus, exhibiting hyperactivation of CTLs and antigen-presenting cells, and inadequate restriction of viral proliferation. In contrast, neither Listeria monocytogenes nor MCMV induces the syndrome. In mice, the HLH phenotype is conditional, which suggests the existence of a specific infectious trigger of FHL3 in humans.
Crozat
Karine
K
The Scripps Research Institute (TSRI), La Jolla, CA 92037, USA.
Hoebe
Kasper
K
Ugolini
Sophie
S
Hong
Nancy A
NA
Janssen
Edith
E
Rutschmann
Sophie
S
Mudd
Suzanne
S
Sovath
Sosathya
S
Vivier
Eric
E
Beutler
Bruce
B
D000818:Animals; D000938:Antigen-Presenting Cells / Q000378:metabolism; D017209:Apoptosis; D003001:Cloning, Molecular; D004195:Disease Models, Animal; D020022:Genetic Predisposition to Disease; D006566:Herpesviridae Infections / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D007371:Interferon-gamma / Q000096:biosynthesis; D051359:Lymphohistiocytosis, Hemophagocytic / Q000145:classification / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018146:Muromegalovirus / Q000502:physiology*; D009154:Mutation / Q000235:genetics; D010641:Phenotype
D008565:Membrane Proteins; C520225:Unc13d protein, mouse; D007371:Interferon-gamma