Genetic background influences the extent and severity of cilia-related congenital anomalies in Ift56/Ttc26 mutant mice.

Multiple congenital anomalies have been linked to defects in the formation or function of a small cellular organelle called the cilium. The severity of cilia-related syndromes (ciliopathies) ranges from viable with fertility defects to embryonic lethal, often with different mutations in the same gene resulting in highly variable phenotypes. While some of the disparity is likely due to differential effects of specific mutations, genetic variants at other loci could serve as ciliopathy modifiers. This could lead to the same mutation causing distinct effects in different individuals. Here, we show that a loss-of-function mutation in Ift56, a key gene involved in cilia protein trafficking, has dramatic phenotypic differences depending on the genetic background in mice. It has previously been reported that in the Balb/cByJ background, Ift56hop homozygous mutants are viable as adults, males are sterile, and homozygotes move their hindlimbs in tandem, resulting in a hopping gait. In contrast, we demonstrate that in the C57BL/6J background, Ift56hop homozygotes are perinatal lethal, and have multiple skeletal and organ defects, including the formation of tracheoesophageal fistulas. Using Single Nucleotide Polymorphisms (SNPs) that differ between these mouse strains, we show that a modifier of the Ift56hop phenotype maps to Chromosome 4. Mutations in IFT56 and other cilia-related genes are being discovered in a growing number of human patients so understanding the mechanisms of their pathology is critical. Our study highlights the use of mouse models to identify ciliopathy modifier loci, with direct implications for human diagnostics.