Genetics and pathophysiology of human asthenozoospermia – Identification and functional characterization of IQCH

Emma Cavarocchi

23 January 2023

Thesis defence

Pratical info

14:00 -
Conference room Rosalind Franklin
research professional
Reduced mobility access

Under the supervision of Aminata Touré, team from gametes to birth

Human male infertility most frequently derives from the absence or reduction of sperm motility, a condition calledasthenozoospermia. Indeed, sperm morphological and/or functional defects can preclude proper sperm progression through the female genital tract and oocyte fertilization. While many genes with causal mutations have beenidentified in the case of human asthenozoospermia due to severe sperm morphological defects, the genetic aetiology of functional asthenozoospermia is still poorly defined.In this context, my thesis significantly contributed to this research field by exploring the involvement of threecandidate genes in human and mouse conditions of asthenozoospermia. I first characterized mutations in the Na+/H+ exchanger SLC9C1, the Microtubule-Interacting Protein MAP7D3, and IQCH, encoding for a protein of unknown function. I demonstrated the pathogenicity of the identified mutations and confirmed their deleterious impact on sperm transcripts and proteins in samples from the patients. Besides and most interestingly, I focused my thesis work on the characterisation of IQCH, a novel gene for which very few information was so far reported in the literature. This gene encodes for a protein with a Calmodulin-binding IQ motif and several enzymatic features, which suggest a function in sperm cells at the intersection of calcium signalling and energy metabolism. I characterized the different encoded isoforms of IQCH and, using high-resolution microscopy, I showed a unique helical distribution of the protein within the axoneme of the sperm flagellum. I next analysed a mutant mouse model lacking the IQ motif and observed a phenotype of oligoasthenoteraotozoospermia, confirming the essential role ofIQCH for male fertilization potential.
Overall, my thesis project allowed the identification of novel genetic causes of male infertility due to functional asthenozoospermia. These data will be useful for the molecular diagnosis of this pathology and for patient management. Importantly, my work also contributed to a better understanding of the molecular mechanisms regulating sperm motility and functional activation.

Keywords: Male infertility, asthenozoospermia, sperm motility, sperm capacitation, IQCH, Calmodulin, SLC9C1, MAP7D3.