ΔF508-Cftrmutation in genetically diverse Collaborative Cross mice yields novel disease-relevant phenotypes for cystic fibrosis

Abstract

AbstractMutations ofCystic Fibrosis Transmembrane conductance Regulator(CFTR) lead to Cystic Fibrosis (CF), but the substantial phenotypic variations are determined by non-CFTRallelic diversity. To map novel disease phenotypes in a CF mouse model, we used Collaborative Cross (CC) mice, a highly genetically diverse mouse resource population.ΔF508-Cftrhomozygosity produced a fully penetrant lethal phenotype by eight weeks in two CC lines. The lethality of CC006ΔF508/ΔF508was fully prenatal while CC037ΔF508/ΔF508showed either prenatal or postnatal lethality. Novel phenotypes of CC037ΔF508/ΔF508were revealed early in life including respiratory and systemic inflammatory profiles, and blood, bone marrow, pancreas, heart, and reproductive tract pathologies. Severe intestinal blockage was observed as common in other CF mouse models. These results suggest that the exploration of CF disease phenotypes in a mouse population with diverse genetic profiles is needed to map the genetic origin of currently unidentified disease traits and their potential translation to humans.