Quantitative trait locus mapping of airway responsiveness to chromosomes 6 and 7 in inbred mice

Abstract

Quantitative trait locus (QTL) mapping was used to identify chromosomal regions contributing to airway hyperresponsiveness in mice. Airway responsiveness to methacholine was measured in A/J and C3H/HeJ parental strains as well as in progeny derived from crosses between these strains. QTL mapping of backcross [(A/J x C3H/HeJ) x C3H/HeJ] progeny (n = 137-227 informative mice for markers tested) revealed two significant linkages to loci on chromosomes 6 and 7. The QTL on chromosome 6 confirms the previous report by others of a linkage in this region in the same genetic backgrounds; the second QTL, on chromosome 7, represents a novel locus. In addition, we obtained suggestive evidence for linkage (logarithm of odds ratio = 1.7) on chromosome 17, which lies in the same region previously identified in a cross between A/J and C57BL/6J mice. Airway responsiveness in a cross between A/J and C3H/HeJ mice is under the control of at least two major genetic loci, with evidence for a third locus that has been previously implicated in an A/J and C57BL/6J cross; this indicates that multiple genetic factors control the expression of this phenotype.

Pulmonary adenoma susceptibility 1 (Pas1) locus affects inflammatory response

“…However, both the A/J and C57BL/6J strains of the cross used to map the Aliq1 locus carry a null allele at the Par1 locus (Manenti et al, 1996), suggesting that the Aliq1 locus is distinct from the Par1 locus. On chromosome 6, the Bhr5 locus, controlling noninflammatory bronchial airway hyper-responsiveness, was mapped in a region proximal (50 cM) to that of the Pas1 locus (74 cM), indicating that these two loci are distinct (De Sanctis et al, 1999;Manenti et al, 1999). More recently, additional loci affecting lung inflammatory response have been mapped on chromosomes 9, 10, 15, and 18 (Malkinson et al, 2002).…”

Mast Cells in Airway Hyporesponsive C3H/HeJ Mice Express a Unique Isoform of the Signaling Protein Ras Guanine Nucleotide Releasing Protein 4 That Is Unresponsive to Diacylglycerol and Phorbol Esters

“…After this hybridization step, the slides were incubated with fluoresceinated antidigoxigenin Ab and counterstained with 4,6-diamidino-2-phenylindole. The data obtained indicated that the mRasGRP4 gene resides at, or near, a site that controls baseline airway reactivity in backcrossed A/J and C3H/ HeJ mice (24). Thus, mBMMCs were generated from A/J and C3H/HeJ mice by culturing their bone marrow progenitors for 2-7 wk in IL-3-enriched medium in the presence or absence of c-kit ligand.…”

“…Many genes (e.g., those that encode IL-4, IL-5, IL-12, IL-13, IL-4R␣, TIM1, bradykinin, ADAM (a disintegrin and metalloprotease) member 33, Fc⑀RI␤, tryptase, leukotriene C 4 synthase, prostaglandin D 2 synthase, and complement 5) have been implicated in this airway disorder. De Sanctis et al (24) noted that baseline airway reactivity to methacholine in inbred C3H/HeJ and A/J mice is dominantly influenced by an unidentified gene on mouse chromosome 7B1 ϳ20 cM from the centromere. This site was not identified in backcrossed A/J and C57BL/6 mice (33).…”

“…Because RasGRP4 influences the final stages of MC development, including what lipid (22) and protease (6) mediators this cell produces, De Sanctis et al (24) raised the possibility that an unusual isoform of mRasGRP4 might be expressed in the MCs of C3H/HeJ mice. RT-PCR analysis (Fig.…”

Sendai virus-induced alterations in lung structure/function correlate with viral loads and reveal a wide resistance/susceptibility spectrum among mouse strains

“…As respiratory pattern/function examination in the mouse by plethysmography yields results far more sensitive and informative than those other techniques can afford when betweenstrains comparison is the aim (17,19,41), we analyzed SeV resistance/susceptibility phenotypes during the first week after infection by simultaneously implementing double-chamber plethysmography, histological evaluation, and lung virus yield assaying techniques. Overall, this approach revealed a pattern of continuous variation, with resistant, intermediate, and susceptible strains, which would be suggestive of a complex trait controlled by several genes.…”