A key component of lung defense is the efficiency of mucociliary clearance (MCC).
Primary ciliary dyskinesia (PCD) is a human genetic disorder with defective MCC. This
ongoing project is designed to identify additional disease-causing mutations in PCD, and
correlate the molecular etiologies with the ciliary phenotype (ultrastructure, wave form
and beat frequency). We have recently shown that the normal human cilium has a
distinctive waveform, i.e. beats in-plane with defined curvatures and amplitudes for the
effective (forward) and recovery stroke. We hypothesize that discrete sets of genes
contribute to the structure and function of the ciliary outer dynein arm (ODA), inner
dynein arm (IDA), and central pair (CP) and radial spoke (RS) complex (CP/RS), and that
we can identify novel genetic mutations in different structural components of the cilium
that will have different effects on ciliary ultrastructure, wave form, and beat
frequency. Importantly, we are now able to identify patients with PCD who do not have
hallmark diagnostic ultrastructural defects, based on distinctive clinical phenotypes
(including situs inversus), low or borderline nasal NO production, and abnormal ciliary
motility. Identification of PCD patients with normal ciliary ultrastructure (~16% of PCD
patients at UNC) offers the opportunity to discover mutations in genes that cause
functional, but not ultrastructural, defects (such as DNAH11), and to correlate those
mutations with ciliary waveform abnormalities. Over the past 4 years, we have made great
progress in identifying mutations in 2 genes (DNAI1 and DNAH5) that cause ~60% of ODA
defects in PCD, and ~35% of PCD overall. We will extend our search for disease causing
mutations in PCD, using several different approaches, including studies of additional
candidate genes, (guided by ultrastructure), plus insights from ciliary proteomics, and
family-based studies. Taken together, these studies will provide new insights regarding
the relationship of mutations in specific genes to ciliary ultrastructural and functional
defects. These studies will not only greatly enhance our ability to diagnose PCD, but
will also lead to discovery of "milder" genetic mutations associated with normal ciliary
ultrastructure, and likely some residual ciliary function. Ultimately, this will allow
future studies of the role of partial loss of ciliary function in the predisposition to
more common airways diseases, such as chronic bronchitis and chronic obstructive
pulmonary disease.