DeltaF508-Cftr mutation in genetically diverse Collaborative Cross mice yields novel disease-relevant phenotypes for cystic fibrosis

Abstract

Mutations of Cystic Fibrosis Transmembrane conductance Regulator (CFTR) lead to Cystic Fibrosis (CF), but the substantial phenotypic variations are determined by non-CFTR allelic diversity. To map novel disease phenotypes in a CF mouse model, we used Collaborative Cross (CC) mice, a highly genetically diverse mouse resource population.{Delta} F508-Cftr homozygosity produced a fully penetrant lethal phenotype by eight weeks in two CC lines. The lethality of CC006{Delta}F508/{Delta}F508 was fully prenatal while CC037{Delta}F508/{Delta}F508 showed either prenatal or postnatal lethality. Novel phenotypes of CC037{Delta}F508/{Delta}F508 were 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.