ClinVar

In a 29-year-old infertile Chinese man (family 1) who had oocyte fertilization failure due to lack of oocyte activation (SPGF53; 619258), Dai et al. (2021) identified homozygosity for a c.1034C-T transition (c.1034C-T, NM_178525.5) in the ACTL9 gene, resulting in a ser345-to-leu (S345L) substitution at a highly conserved residue. His unaffected parents were heterozygous for the mutation, which was not found in 100 fertile men or in the East Asian population of ExAC, but was present at low frequency in the East Asian population of the gnomAD database (5.4 x 10(-5)). Immunostaining of patient sperm revealed that, unlike in normal sperm, ACTL9 signal did not overlap with that of its paralog, ACTL7A (604303). Intensity profiles showed that none of the mutant sperm manifested a strong signal in the equatorial segment, and the acrosome showed no cap structure. Coimmunoprecipitation assay confirmed that the interaction between ACTL9 and ACTL7A was weakened in S345L mutant sperm. Immunostaining in mutant capacitated sperm for a key oocyte activation factor, PLCZ1 (608075), showed absence or abnormal localization in the neck rather than the equatorial segment of the head. Monitoring Ca(2+) oscillations in oocytes injected with mutant sperm showed absence of the Ca(2+) spikes that would normally be seen. Oocytes injected with normal sperm showed diffuse PLCZ1 in the ooplasm with sperm asters forming around the sperm nucleus, and the oocytes exited metaphase II (MII) with extrusion of the second polar body; in contrast, oocytes injected with S345L mutant sperm remained in MII arrest, with some showing PLCZ1 retained around the sperm head and failure to form the sperm aster, and others showing total absence of PLCZ1 signals in the ooplasm or in the area of the sperm nucleus.