PCD is a genetically heterogeneous disease, which is usually inherited in an autosomal recessive manner. For autosomal recessive PCD variants, so far >40 distinct genes have been discovered. PIH1D3 is located on the X chromosome, loss-of-function mutations cause PCD in males.
An X-linked inheritance for PCD is associated with mutations in two other genes, RPGR and OFD1, and are associated with other serious disease manifestations. Our group was significantly involved in the identification of genes marked with a link, whose mutations are associated with PCD. We are actively researching new causative genes for PCD.
From phenotype to candidate gene analysis Primary ciliary dyskinesia is based on the failure of the structural and functional components of cilia and its associated proteins. At least 250 proteins are involved in the coordinated beating of cilia. Mutations in the genes corresponding to each of these 250 proteins could potentially lead to PCD. The genes are sometimes very large, such as axonemal dynein heavy chain 5 (DNAH5) of the outer dynein arm (ODA) component; DNAH5 alone has 80 coding segments (exons). A genetic analysis is therefore very expensive, especially since not all human genes for PCD have been identified yet. In order to find new candidate genes, certain information is required. Linkage analysis (comparing the alleles of healthy and sick family members) provides information on the potential locus of the causative gene. The phenotype can provide clues regarding the function of the defective protein. For example, by high-speed video microscopy analysis, cilia that demonstrate a stiff, trembling beat pattern points to a defect in the inner dynein arms; an only occasional twitching or complete immotility of cilia, however, suggests a defect of the ODA. Immunofluorescence analysis (IF) provides more accurate information about the function and location of the desired gene product. Once a candidate gene is found, all coding gene segments are amplified by PCR and bidirectionally sequenced to identify potential mutations.
Molecular genetic diagnosis
We, in collaboration with the Institute for Human Genetics at the University Hospital of Münster (Univ.-Prof. Dr. P. Wieacker), provide molecular genetic analysis of known genes in patients with PCD. The diagnosis of "PCD" is verified from our laboratory by immunofluorescence microscopy. Please think about the issue of a referral laboratory certificate. Participation in our IF diagnosis is a prerequisite for the implementation of molecular genetic analysis. The consent of the patient includes the participation in our ongoing research. For further information and documentation, see the following links or contact directly our laboratory in Muenster.