DIFFERENT types of mutations in the FBXO43 gene may determine the severity of male infertility and could help guide personalised assisted reproductive strategies, new research suggests.
The study identified distinct FBXO43 variants in two men with severe infertility and found that mutation severity appeared to influence whether sperm production was impaired or completely arrested.
Genetic abnormalities are an important cause of severe male infertility, particularly nonobstructive azoospermia (NOA), in which sperm production is severely impaired or absent.
Researchers in China investigated FBXO43, a gene involved in regulating meiosis, the specialised form of cell division required to produce sperm and eggs.
Whole-exome sequencing was performed in 118 patients with asthenoteratozoospermia, where sperm have both reduced movement and abnormal shapes, and 626 with NOA. Two unrelated patients were identified with rare compound heterozygous variants in FBXO43.
One patient, who had macrozoospermia (sperm with misshaped, abnormally large heads) carried two missense variants, p.Pro641Leu and p.Arg660Gln. The second patient, diagnosed with NOA, carried a nonsense variant and a frameshift variant that were predicted to truncate the FBXO43 protein and remove an important functional region.
The patient with the missense variants was able to produce sperm, but sperm quality was severely impaired. Only 13.56% of sperm showed progressive motility and 3.3% had normal morphology.
The patient had experienced infertility for 10 years and undergone seven intracytoplasmic sperm injection (ICSI) cycles at five reproductive centres. Across 19 embryo transfers, only one clinical pregnancy occurred, which subsequently ended in early miscarriage.
Further analysis showed enlarged sperm heads, defective chromatin condensation, and substantially increased aneuploidy, indicating abnormalities in chromosome number.
By contrast, the patient with truncating FBXO43 variants had NOA. Testicular analysis suggested meiotic arrest, with no mature sperm produced.
Laboratory experiments indicated that all four variants reduced the stability of the FBXO43 protein and disrupted its interaction with APC3, a component of the anaphase-promoting complex/cyclosome (APC/C), which plays a central role in chromosome segregation during cell division.
The findings suggest that FBXO43-related infertility may exist along a spectrum rather than producing a single clinical phenotype.
The researchers propose that less severe missense mutations may allow meiosis to be completed, but produce sperm with major chromosomal and structural abnormalities. More disruptive truncating variants, meanwhile, may prevent meiosis from being completed altogether, resulting in azoospermia.
This distinction could potentially influence reproductive counselling. Where sperm production is preserved but aneuploidy is high, the authors suggest that preimplantation genetic testing for aneuploidy may be considered to help select embryos. In individuals with severe loss-of-function variants and no usable sperm, alternative reproductive options may be required.
However, the findings are based on just two affected individuals, substantially limiting the conclusions that can be drawn. Functional experiments were also conducted in HEK293T cells rather than human germ cells and therefore cannot fully reproduce the biological environment of the testis.
The researchers conclude that larger studies are needed but suggest that identifying specific FBXO43 variants could eventually help explain differences in spermatogenic failure and support more individualised reproductive counselling.
Xiao Y et al. Mutation Severity of FBXO43 Determines Spermatogenic Outcome and Informs Precision ART Strategies. Human Mutation. 2026;2026:7905936.
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