A loss-of-function variant in SSFA2 causes male infertility with globozoospermia and failed oocyte activation

Huang, Gelin, Zhang, Xueguang, Yao, Guanping, Huang, Lin, Wu, Sixian, Li, Xiaoliang, Guo, Juncen, Wen, Yuting, Wang, Yan, Shang, Lijun, Li, Na and Xu, Wenming (2022) A loss-of-function variant in SSFA2 causes male infertility with globozoospermia and failed oocyte activation. Reproductive Biology and Endocrinology, 20 (103). pp. 1-13. ISSN 1477-7827


Globozoospermia (OMIM: 102530) is a rare type of teratozoospermia (< 0.1%). The etiology of globozoospermia is complicated and has not been fully revealed. Here, we report an infertile patient with globozoospermia. Variational analysis revealed a homozygous missense variant in the SSFA2 gene (NM_001130445.3: c.3671G > A; p.R1224Q) in the patient. This variant significantly reduced the protein expression of SSFA2. Immunofluorescence staining showed posi- tive SSFA2 expression in the acrosome of human sperm. Liquid chromatography–mass spectrometry/mass spectrom- etry (LC–MS/MS) and Coimmunoprecipitation (Co-IP) analyses identified that GSTM3 and Actin interact with SSFA2.

Further investigation revealed that for the patient, regular intracytoplasmic sperm injection (ICSI) treatment had a poor prognosis. However, Artificial oocyte activation (AOA) by a calcium ionophore (A23187) after ICSI successfully rescued the oocyte activation failure for the patient with the SSFA2 variant, and the couple achieved a live birth. This study revealed that SSFA2 plays an important role in acrosome formation, and the homozygous c.3671G > A loss-of-function variant in SSFA2 caused globozoospermia. SSFA2 may represent a new gene in the genetic diagnosis of globozoospermia, especially the successful outcome of AOA-ICSI treatment for couples, which has potential value for clinicians in their treatment regimen selections.

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