Junyan Chen, Yisi Sun, Tong Zhou, Jing Zhou, Minmin Hua, Miao Liu, Xiaorong Shen, Jianan Tang, Xuemei Wang, Huijuan Shi, Yongning Lu, Aijie Xin
These findings suggest an expansion of the genotypic and phenotypic spectrum of FSIP2-associated male infertility. In the two cases studied, biallelic FSIP2 variants were associated with classical MMAF and acrosomal abnormalities, as well as with abnormal nuclear ultrastructure and increased CMA3 staining indicative of impaired chromatin condensation. However, further studies are needed to establish whether these nuclear features represent a direct consequence of FSIP2 deficiency.
PURPOSE: Biallelic variants in FSIP2 have been associated with multiple morphological abnormalities of the sperm flagella (MMAF) and acrosomal defects. This study aimed to characterize the genetic, sperm phenotypic, and reproductive features of infertile men carrying homozygous FSIP2 variants, with particular attention to sperm nuclear ultrastructure and chromatin condensation.
METHODS: Two infertile men with severe sperm morphological abnormalities were enrolled. Whole-exome sequencing and Sanger sequencing were performed to identify candidate variants. Sperm morphology, FSIP2 expression, acrosomal status, nuclear ultrastructure, and chromatin condensation were evaluated using routine semen analysis, immunofluorescence staining, transmission electron microscopy, and chromomycin A3 (CMA3) staining. Intracytoplasmic sperm injection outcomes were reviewed.
RESULTS: Two homozygous FSIP2 variants were identified in two men with primary infertility, including a frameshift variant, NM_173651.3: c.2519delA, p.(Asn840Metfs*43), and a missense variant, NM_173651.3: c.17798C > T, p.(Ser5933Phe). The missense variant, previously reported in a compound heterozygous context, was identified here in a homozygous state. Spermatozoa from both patients exhibited typical MMAF phenotypes and markedly reduced or absent FSIP2 signals. Acrosomal loss or abnormal acrosomal localization was also observed. Notably, spermatozoa from both patients showed prominent intranuclear vacuoles and increased CMA3 staining, suggesting defective chromatin condensation. After ICSI, both couples achieved fertilization, and one couple achieved a live birth.
CONCLUSIONS: These findings suggest an expansion of the genotypic and phenotypic spectrum of FSIP2-associated male infertility. In the two cases studied, biallelic FSIP2 variants were associated with classical MMAF and acrosomal abnormalities, as well as with abnormal nuclear ultrastructure and increased CMA3 staining indicative of impaired chromatin condensation. However, further studies are needed to establish whether these nuclear features represent a direct consequence of FSIP2 deficiency.