A Homozygous NUP210L Variant Is Associated With Severe Defects in Human Spermiogenesis

Area of Science:

• Reproductive biology
• Human genetics
• Cell biology

Background:

• Spermiogenesis, essential for male fertility, involves complex nuclear and cytoplasmic changes.
• Genetic factors causing human spermiogenic failure are not fully understood.
• NUP210L, a testis-specific nucleoporin, is implicated in male infertility, but human data is limited.

Purpose of the Study:

• Investigate the genetic cause of severe oligoasthenoteratozoospermia (OAT) in a patient with a NUP210L variant.
• Characterize the spermiogenic defects and fertilization impact of this NUP210L variant.
• Evaluate the potential of artificial oocyte activation (AOA) to restore fertility.

Main Methods:

• Whole-exome sequencing identified a homozygous NUP210L deletion in a consanguineous family.
• Sperm analysis included electron microscopy, immunofluorescence, and chromatin staining (Chromomycin A3).
• Intracytoplasmic sperm injection (ICSI) with and without AOA assessed fertilization outcomes.

Main Results:

• A homozygous NUP210L deletion (p.Ser501del) was identified in the affected male.
• Patient sperm showed defects in chromatin condensation, acrosome, mitochondria, and fibrous sheath.
• NUP210L mislocalization, not reduced expression, correlated with functional impairment.
• Defective nuclear remodeling (histone retention) and absence of PLCζ led to total fertilization failure with conventional ICSI.
• ICSI with AOA successfully restored fertilization and blastocyst development.

Conclusions:

• A homozygous NUP210L variant causes severe human spermiogenic defects and male infertility.
• NUP210L plays a crucial role in human spermiogenesis, with a phenotype not fully mirrored in mouse models.
• NUP210L dysfunction impairs sperm's oocyte activating ability, suggesting nucleoporin defects contribute to infertility.
• AOA offers a potential therapeutic strategy for fertilization failure in such cases.