Mutations in the dynein assembly factor PF22 (DNAAF3) cause primary ciliary dyskinesia with absent dynein arms

摘要

The genetic disorder primary ciliary dyskinesia (PCD)arises from dysmotility of cilia in the respiratory tract,brain ventricles, oviduct and the embryonic node. Patientshave chronic obstructive pulmonary disease, reduced fertilityand situs abnormalities. PCD is genetically heterogeneouswith 12 genes causing ~40% of all cases, twoencoding proteins (KTU, LRRC50) involved in cytosolicaxonemal dynein co-assembly. We have identified mutationsin the C19ORF51 gene located within a previouslymapped PCD locus. C19ORF51 encodes a protein orthologousto PF22, a Chlamydomonas protein involved in thecytoplasmic assembly of outer dynein arms preceedingtheir import into the axoneme. Chlamydomonas pf22 cellsdisplay a disturbance in their cytoplasm of dynein heavychain stability and the co-assembly of heavy with intermediatechains, both essential for dynein arm assembly.PF22 appears to act downstream of KTU and LRRC50in the dynein preassembly pathway. PF22 knockdown inzebrafish causes a loss of dynein arms, cilia dysmotility,and a typical ciliopathy phenotype with axis curvature,pronephric cysts, hydrocephalus and situs inversus. Wepropose the existance of a conserved multi-step pathwayfor formation of assembly-competent dynein complexes,and that PF22 (now renamed DNAAF3, “dynein axonemalassembly factor 3”) mutations cause PCD with situs inversusdue to deficient cytoplasmic dynein assembly which inturn leads to missing outer arms in the axoneme.