Molecular defects in multiple morphological abnormalities of the sperm flagellum (MMAF)

• Applicant: Dr. Johanna Raidt
• Subject Area: Reproductive Medicine, Urology
• Term: since 2020
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 329621271

Recently, a severe form of morphological defects of sperm flagella including a mosaic of absent, short, bent, coiled, and irregular flagella was newly termed ‘Multiple Morphological Abnormalities of the sperm Flagella’ (MMAF). It results in significantly decreased sperm motility (asthenozoospermia) displaying a frequent cause for male infertility. MMAF is a heterogeneous disease with rapidly increasing identification of genetic causes. But knowledge on molecular composition and function of most MMAF associated components remains poorly understood. Another heterogeneous disease caused by defects of diverse axonemal components is Primary Ciliary Dyskinesia (PCD). It is characterized by reduced mucociliary clearance leading to recurrent infections of the airways. As sperm flagella and motile cilia comprise an evolutionary conserved, similar axonemal structure, PCD is closely associated with male infertility. In the multidisciplinary case conference within the CRU326, we detected several men presenting MMAF. In two men, we identified homozygous mutations in DNAH1, which is a common cause of MMAF. Both displayed no severe respiratory phenotype, while we showed the lack of DNAH1 in the sperm flagella as well as respiratory cilia and a slightly abnormal ciliary beating. We recently demonstrated, that mutations in one of MMAF gene, SPEF2, also lead to severe respiratory symptoms. Besides diagnosing another infertile male with MMAF due to a homozygous mutation in CFAP43 showing no respiratory symptoms, we found a severe respiratory phenotype in a 3-year-old girl also carrying homozygous CFAP43 mutations. Furthermore, we detected a MMAF-like phenotype in a PCD male with mutations in CCDC39. Altogether, our findings strongly suggest, that distinct MMAF variants comprise further disease manifestations, such as lung disease. Within this approach, we will recruit MMAF males for distinct pneumological evaluation and genetic analysis. As fertility status of most PCD variants remains unclear, we also recruit PCD males for andrological assessment. In all MMAF and PCD males, molecular characterization of sperm flagella and respiratory cilia will be performed to determine underlying disease mechanisms including novel genetic causes leading to male infertility due to MMAF. A critical genotype/phenotype-correlation will enhance the clinical and molecular understanding of MMAF and PCD. Translation of study results into patient care will improve diagnostics and raise the awareness of associated symptoms in MMAF with substantial benefit for the health status of patients.

• DFG Programme: Clinical Research Units
• Subproject of: KFO 326: Male Germ Cells: from Genes to Function