International Mammalian Genome Society

The 14th International Mouse Genome Conference (2000)

G19. Detection of Modifier Loci influencing the Lung Phenotype of Cystic Fibrosis Knockout Mice

C.K. Haston, C. McKerlie, T. Samanta, B. Budisin, G. Kent, M. Corey, R. Rozmahel and L-C. Tsui.
The Hospital for Sick Children, Toronto, Ontario, Canada

The majority of cystic fibrosis patients develop pulmonary disease but the severity of this complication appears to be independent of CFTR genotype. To investigate if the CF associated lung disease is influenced, in part, by modifier genes we exploited a CFTR-knockout mouse model of a congenic C57BL/6J background, B6 CF, in which a consistent lung phenotype could be observed. These characteristics were not detected in CF mice of other genetic backgrounds, including BALB/cJ, nor in their wild type sibs maintained in identical environments. Therefore, it should be possible to identify the genetic factor(s) associated with predisposition of lung disease, through a genome wide scan for quantitative trait loci (QTL) contributing to the observed differences in CF-associated lung disease between B6 and BALB CF mice. Two hundred and sixteen F2 (by F1 intercross) CF mice have been produced and were found to present a range of lung disease. The pulmonary phenotype was characterized in 3 ways: a semi quantitative histological method based on the extent and severity of left lung alveolar interstitial thickening; image analysis of fibrotic area per lung tissue area in a histological section, and myeloperoxidase levels in the right lung as an index of neutrophil influx. Preliminary data have been obtained for 135 DNA markers, at 15 cM spacing, for all F2 mice. The QTL analysis revealed suggestive linkage for each of the phenotypes. The preliminary scan is being followed up with more markers in the regions of suggestive linkage.

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