| Primary Ciliary Dyskinesia (PCD) is responsible for respiratory disorders, male infertility and female subfertility, as well as body plan defects that occur during development. Defects associated with PCD are often associated with dynein subunit mutations, however ciliary motility is also dependent on effective signaling to dyneins from two interacting regulatory structures, the central pair and the radial spokes, through a Dynein Regulatory Complex. Some cases of PCD result from radial spoke or central pair defects. We isolated a novel central pair mutant that displays a reduced flagellar beat frequency, aberrant swimming pattern and loss of central pair structures associated with C2 microtubule instability. Of particular interest, this mutant has an unusual flagellar coordination between the cis and trans flagella, a phenotype associated with some radial spoke head mutants or with loss of the central pair protein hydin. The presence of this phenotype in a central
pair mutant suggests a direct interaction between the missing structures along the C2 microtubule and radial spoke heads. Using Mendelian genetic analysis, we mapped the mutation to a previously uncharacterized locus on linkage group V, which we named uncoordinated 1 (UNC1). Using molecular mapping, BAC rescue and subcloning methods, the UNC1 gene product has been identified as a subtilisin-like serine protease. There are no previously published reports of any protease being present in flagella. While it is clear that UNC1 is involved in central pair assembly, we are currently in the process of determining if this protein is predominately present in the cytoplasm or the flagella, and whether protease activity is essential for its function. We hypothesize that UNC1 is necessary to proteolytically modify central pair components prior to assembly. Supported by National Institutes of General Medical Sciences grant GM44228 to DRM. |