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Primary ciliary dyskinesia and human gene mutations

Primary Ciliary Dyskinesia (PCD) is a genetic disorder affecting 1 in 15,000 births that causes cilia paralysis with left-right organ asymmetry defects, bronchiectasis, sinusitis, and infertility. We positionally cloned a novel zebrafish cilia paralysis gene, schmalhans / ccdc103, and then showed that human patient families with PCD carried mutations in the orthologous human gene, identifying a novel cause of PCD. We also developed an in vivo assay to test pathogenicity of candidate human disease alleles by mRNA injection rescue of the zebrafish phenotype. This work defined a new human disease gene and established the fish as an in vivo assay system for distinguishing pathogenic human gene mutations from benign sequence polymorphisms.

The cilia proteome contains over 600 proteins, many with unknown function. Using a reverse genetic screen in zebrafish, we identified two genes, C21orf59 and CCDC65, as new causes ciliopathy and lead a consortium to establish the function of these genes in other organisms including humans. Our consortium showed that these two genes were essential for cilia motility in Chlamydomonas, planaria, zebrafish, and importantly, human PCD families. This work substantiated the use of zebrafish as a broadly relevant discovery platform and defined novel protein functions in cilia dynein motor assembly and regulation.

In addition, we  collaborate with mammalian geneticists to test candidate mouse and human disease mutations implicated in the kidney disease juvenile nephronophthisis by establishing orthologous gene function in zebrafish. Juvenile nephronophthisis is the most common disease leading to kidney failure in children. Our contributions overcome the difficulty of assigning function to many human candidate genes in large genetic intervals by establishing a functional test in zebrafish.