Characterization of a DRC1 null variant associated to primary ciliary dyskinesia and female infertility

Background: Primary ciliary dyskinesia (PCD; MIM #242650) is a rare multisystemic genetic diseases, whose diagnostic is challenge. Additional data to complete the complex puzzle of PCD genomic analysis is of upmost importance to better understand PCD pathophysiology. We here present a female case with PCD and infertility. We also present the evaluation of the patient family, including her twin sister, also with PCD and infertility. Methods: Confirmation of the PCD clinical diagnosis was performed through assessment of cilia motility, by high-speed video microscopy (HSVM), axoneme ultrastructure, by transmission electron microscopy (TEM), and genetic characterization, by whole exome sequence (WES). Gene expression studies used qPCR for mRNA expression and immunofluorescence to determine cell protein localization. Results: HSVM analysis revealed that the ciliary beat frequency was decreased, with mostly cilia presenting dyskinetic movements. TEM analysis showed partial absence of both dynein arms associated with high ciliary deviation. WES analysis evidenced a homozygous nonsense variant in the DRC1 gene, belonging to the dynein regulatory complex (DRC). Expression of DRC1 mRNA and protein were decreased. Expression analysis of the DRC1 mRNA also evidenced an interaction with other DRC components. Family analysis revealed the same homozygous variant in the twin sister and, in heterozygosity in parents and daughters. Both the patient and her twin sister presented idiopathic infertility. Conclusions: Overall, our results contribute to increase understanding of the genetic factors involved in the pathophysiology of PCD and infertility, and highlight the interaction of different genes in the patient phenotype, which should be further explored, as it may justify the highly heterogeneity observed in PCD patients. Understanding the genetic etiology of PCD is of paramount importance to assist the diagnosis and development of newer therapies.