Compound Heterozygous Mutations in FSIP2 Cause Morphological Abnormalities in Sperm Flagella Leading to Male Infertility

Multiple morphological abnormalities of sperm flagella (MMAF) indicate severe teratozoospermia. The fibrous sheath interacting protein 2 (FSIP2) plays an important role in the normal construction of the flagella. In this study, a novel compound heterozygous mutation site of FSIP2, involving c.272_275delinsAGGTTTTTATA (p.L92Vfster74) and c.16788_16791del (p.E5596fs), was identified using whole-exome sequencing in a 32-year-old male. Electron microscope images revealed thick sperm neck, scattered sperm mitochondria, and short sperm tail. In addition, FSIP2 could not be visualized in sperm cells via immunofluorescence staining. Moreover, we used a protein domain prediction tool to identify a potential FSIP2 functional domain (5901-6774), the corresponding deletion of which was responsible for the MMAF phenotype in the infertile man. Finally, we reviewed the literature on FSIP2 and found that FSIP2 mutations are relatively concentrated, with high-frequency mutation regions in exon 16 and exon 17 accounting for 50% (10/20) and 35% (7/20) of cases, respectively. In conclusion, FISP2 is a common pathogenic gene of MMAF, which may provide a rationale for genetic counseling in the next generation of patients with male infertility.