Loss-of-function mutations in a human gene related to Chlamydomonas reinhardtii dynein IC78 result in primary ciliary dyskinesia

Primary ciliary dyskinesia (PCD) is a group of heterogeneous disorders of u nknown origin, usually inherited as an autosomal recessive trait. Its pheno type is characterized by axonemal abnormalities of respiratory cilia and sp erm tails leading to bronchiectasis and sinusitis, which are sometimes asso ciated with situs inversus (Kartagener syndrome) and male sterility. The ma in ciliary defect in PCD is an absence of dynein arms. We have isolated the first gene involved in PCD, using a candidate-gene approach developed on t he basis of documented abnormalities of immotile strains of Chlamydomonas r einhardtii, which carry axonemal ultrastructural defects reminiscent of PCD . Taking advantage of the evolutionary conservation of genes encoding axone mal proteins, we have isolated a human sequence (DNAI1) related to IC78, a C. reinhardtii gene encoding a dynein intermediate chain in which mutations are associated with the absence of outer dynein arms. DNAI1 is highly expr essed in trachea and testis and is composed of 20 exons located at 9p13-p21 . Two loss-of-function mutations of DNAI1 have been identified in a patient with PCD characterized by immotile respiratory cilia lacking outer dynein arms. In addition, we excluded linkage between this gene and similar PCD ph enotypes in five other affected families, providing a clear demonstration o f locus heterogeneity. These data reveal the critical role of DNAI1 in the development of human axonemal structures and open up new means for identifi cation of additional genes involved in related developmental defects.