A point mutation in the neu1 promoter recruits an ectopic repressor, Nkx3.2 and results in a mouse model of sialidase deficiency.
SM/J is an inbred mouse strain with a complex phenotype including small body size, impaired immune response and a tissue-specific sialidase deficiency. We identified a regulatory mutation, (-519G-->A) within the neu1 promoter which in reporter assays resulted in significantly reduced transcription. This mutation generates a consensus binding site for Nkx3 family transcription repressors. Recombinant Nkx3.2 bound strongly to and preferentially repressed transcription of the mutant promoter. This tissue-specific deficiency results in a retarded immune response and modulates leukocyte recruitment. Examination of the hepatic microcirculation in mutant mice revealed increased rolling and decreased adhesion of leukocytes. Our findings support a significant role for lysosomal sialidase in inflammation and highlight the significance of repressor-recruitment in genetic disease.
Champigny
Marc J
MJ
Department of Biology, McMaster University, Hamilton, Ont., Canada L8S 4K1.
Mitchell
Mark
M
Fox-Robichaud
Alison
A
Trigatti
Bernardo L
BL
Igdoura
Suleiman A
SA
D000818:Animals; D001483:Base Sequence; D002460:Cell Line; D002465:Cell Movement; D004247:DNA / Q000378:metabolism; D004195:Disease Models, Animal; D024202:Electrophoretic Mobility Shift Assay; D018398:Homeodomain Proteins / Q000378:metabolism*; D007249:Inflammation / Q000201:enzymology; D007962:Leukocytes / Q000166:cytology; D008099:Liver / Q000098:blood supply / Q000166:cytology; D051379:Mice; D008833:Microcirculation; D008969:Molecular Sequence Data; D009439:Neuraminidase / Q000172:deficiency* / Q000235:genetics*; D009928:Organ Specificity; D017354:Point Mutation / Q000235:genetics*; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D012097:Repressor Proteins / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism*; D014158:Transcription, Genetic
D018398:Homeodomain Proteins; C107965:Nkx3-2 protein, mouse; D012097:Repressor Proteins; D014157:Transcription Factors; D004247:DNA; C110128:Neu1 protein, mouse; D009439:Neuraminidase