PCDfert · Identification of novel genes and mechanisms for PCD and male infertility

Identification of novel genes and mechanisms for PCD and male infertility

Primary ciliary dyskinesia (PCD) is a heterogenous respiratory disease, which prevalence in Europe is estimated as 1 in 10,000. Improved availability of DNA testing would provide a definitive diagnostic tool for patients, since PCD is underdiagnosed due to lack of knowledge of genetic causes as well as sometimes inconclusive pathology-based tests based upon cilia beating and ultrastructure. This is partly due to its genetic heterogeneity since causal PCD mutations in >40 genes account for 70% of cases. Furthermore, although male infertility has been linked to PCD, it does not affect all patients. Therefore, it is important to identify novel PCD genes and establish the effect of specific PCD mutations on male infertility. The first project objective was to provide training for the Researcher in implementing a patient cohort study for identification of causative mutations in human health issues. Causative mutations for Finnish PCD patient cohort were identified enabling development of DNA tests for diagnostics. Second objective was the characterization of sperm phenotypes in PCD patients. During the project the Researcher organized the sperm sample collection and analysis. Sperm tail structural changes were characterized for patients with known gene mutations. In the third objective the Researcher familiarized with super resolution microscopy techniques during studies of ciliary transition zone components in sperm. Role of intraflagellar transport (IFT) in transition zone formation was studied using Tctex1d2 mutant mouse model and Cep164 conditional knock-out demonstrated the importance of transition fibers in sperm tail formation. Conclusions The MSCA fellowship has enabled development of a collaboration network with world leading scientists and clinicians in the field of cilia research and expertise in clinical studies and human molecular biology. For the first time the link between ciliopathies and male infertility and related molecular mechanisms have been investigated consistently. This has produced unique and timely opportunities to prepare research funding applications for further experiments in the field. Results gained from the fellowship provide insights into protein transport mechanisms during spermiogenesis and genetic causes of PCD and related male infertility.

Data: CORDIS, © European Union