Gene-environment interactions in a mutant mouse kindred with native airway constrictor hyperresponsiveness

Area of Science:

• Genetics
• Immunology
• Environmental Science

Background:

• Airway hyperresponsiveness (AHR) is a hallmark of asthma and other respiratory diseases.
• Genetic factors are known to contribute to AHR susceptibility, but environmental influences are also critical.
• The BTBR mouse strain was used to investigate the genetic basis of AHR.

Purpose of the Study:

• To identify and characterize a novel genetic mutation causing AHR in mice.
• To investigate the role of environmental factors in the expression of the AHR phenotype.
• To understand the implications of environmental conditions on genetic studies of AHR.

Main Methods:

• Chemical mutagenesis of male BTBR mice using N-ethyl-N-nitrosourea.
• Screening of G3 offspring for airway hyperresponsiveness using methacholine challenge.
• Breeding and phenotyping of mutant mice across multiple generations (G3-G12) under varying facility conditions.
• Rederivation of mutant mice into a specific-pathogen-free (SPF) facility.

Main Results:

• A semidominant autosomal mutation conferring AHR with strong gender restriction (males affected, females not) was identified.
• The AHR phenotype disappeared in subsequent generations after facility infection eradication and bedding change from softwood to hardwood.
• The AHR phenotype could not be re-established in mutant mice rederived into an SPF facility.
• These findings indicate that both genetic and environmental factors are necessary for AHR phenotype expression.

Conclusions:

• Environmental factors, such as pathogen exposure and bedding type, critically influence the penetrance of the AHR mutation.
• SPF conditions may mask the genetic susceptibility to AHR, complicating gene discovery efforts.
• Consistent multigenerational animal care and environmental conditions are essential for cloning mutant genes and studying complex phenotypes.