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

Abstract

The genetic disorder primary ciliary dyskinesia (PCD) arises from dysmotility of cilia in the respiratory tract, brain ventricles, oviduct and the embryonic node. Patients have chronic obstructive pulmonary disease, reduced fertility and situs abnormalities. PCD is genetically heterogeneous with 12 genes causing ~40% of all cases, two encoding proteins (KTU, LRRC50) involved in cytosolic axonemal dynein coassembly. We have identified mutations in the C19ORF51 gene located within a previously mapped PCD locus. C19ORF51 encodes a protein orthologous to PF22, a Chlamydomonas protein involved in the cytoplasmic assembly of the outer dynein arms preceding their import into the axoneme. pf22 mutant flagella display a disturbance in their cytoplasm of dynein heavy chain stability and the co-assembly of heavy with intermediate chains, both essential for dynein arm assembly. PF22 appears to act downstream of KTU and LRRC50 in the dynein preassembly pathway. PF22 knockdown in zebrafish causes a loss of the dynein arms, cilia dysmotility, and a typical ciliopathy phenotype with axis curvature, pronephric cysts, hydrocephalus and situs inversus. We propose the existance of a conserved multi-step pathway for formation of assembly-competent dynein complexes, and that PF22 (now renamed DNAAF3, 'dynein axonemal assembly factor 3') mutations causes PCD with situs inversus due to deficient cytoplasmic dynein assembly.