Centrosomal proteins are necessary components of the centrosome, a conserved eukaryotic organelle essential to the reproductive process. However, few centrosomal proteins have been genetically linked to fertility. Herein we identify a homozygous missense variant of CEP128 (c.665 G > A [p.R222Q]) in two infertile males. Remarkably, male homozygous knock-in mice harboring the orthologous CEP128R222Q variant show anomalies in sperm morphology, count, and motility. Moreover, Cep128 knock-out mice manifest male infertility associated with disrupted sperm quality. We observe defective sperm flagella in both homozygous Cep128 KO and KI mice; the cilia development in other organs is normal—suggesting that CEP128 variants predominantly affected the ciliogenesis in the testes. Mechanistically, CEP128 is involved in male reproduction via regulating the expression of genes and/or the phosphorylation of TGF-β/BMP-signalling members during spermatogenesis. Altogether, our findings unveil a crucial role for CEP128 in male fertility and provide important insights into the functions of centrosomal proteins in reproductive biology.

• The transforming growth factor (TGF)-β/SMAD3 signaling pathway greatly influences susceptibility to Kawasaki disease (KD) and secondary coronary artery lesions (CALs) and/or the treatment response of intravenous immunoglobulin. • A disintegrin and metalloprotease 17 (ADAM17) effectively reduces TGF-β signaling by cleaving TGF-β receptor type-1, while ADAM17 genetic variants modify human vascular pathology by differentially regulating this signaling although it is unknown whether ADAM17 contributes to KD phenotypes. What is New: • ADAM17 genetic variants were shown to be associated with KD risk, even when excluding the influence of TGF-β signaling pathway genes, suggesting that ADAM17 is an important KD susceptibility-related genetic locus. • The more significant compound effects of two-locus models, combining single nucleotide polymorphisms (SNPs) in ADAM17 and other TGF-β signaling pathway genes including TGFB2 and SMAD3, on KD phenotypes relative to single SNPs suggest that ADAM17 is also involved in secondary CAL formation and confers the risk of KD/CALs via the TGF-β/SMAD3 signaling pathway.

Testis-specific protein, Y-encoded, 1 (TSPY1) is involved in the regulation of spermatogenic efficiency via highly variable copy dosage, with dosage deficiency of the multicopy gene conferring an increased risk of spermatogenic failure. TSPY-like 1 (TSPYL1) and TSPY-like 5 (TSPYL5), two autosomal homologous genes originating from TSPY1, share a core sequence that encodes a functional nucleosome assembly protein (NAP) domain with TSPY1. To explore the potential effects of TSPYL1 and TSPYL5 on the TSPY1-related spermatogenic phenotype, we investigated the expression of these genes in 15 healthy and nonpathological human tissues (brain, kidney, liver, pancreas, thymus, prostate, spleen, muscle, leucocytes, placenta, intestine, ovary, lung, colon and testis) and explored associations between their variations and spermatogenic failure in 1558 Han Chinese men with different spermatogenic conditions, including 304 men with TSPY1 dosage deficiency. TSPYL1 and TSPYL5 were expressed in many different tissues, including the testis. An unreported rare variant that is likely pathogenic (c.1057A>G, p.Thr353Ala) and another of uncertain significance (c.1258C>T, p.Arg420Cys) in the NAP-coding sequence of TSPYL1 were observed in three spermatogenesis-impaired patients with heterozygous status. The distribution differences in the alleles, genotypes and haplotypes of eight TSPYL1- and TSPYL5-linked common variants did not reach statistical significance in comparisons of patients with spermatogenic failure and controls with normozoospermia. No difference in sperm production was observed among men with different genotypes of the variants. Similar results were obtained in men with TSPY1 dosage deficiencies. Although the distribution of missense variants of TSPYL1 found in the present and other studies suggests that patients with spermatogenic failure may have a statistically significant greater burden of rare variations in TSPYL1 relative to normozoospermic controls, the functional evidence suggests that TSPYL1 contributes to impaired spermatogenesis. Moreover, the present study suggests that the effects of TSPYL1 and TSPYL5 on the spermatogenic phenotype of TSPY1 dosage deficiency are limited, which may be due to the stability of their function resulting from high sequence conservation.

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The testis‐specific protein, Y‐linked 1 ( TSPY 1), a newly recognized cancer/testis antigen, has been suggested to accelerate tumor progression. However, the mechanisms underlying TSPY 1 cancer‐related function remain limited. By mining the RNA sequencing data of lung and liver tumors from The Cancer Genome Atlas, we found frequent ectopic expression of TSPY 1 in lung adenocarcinoma ( LUAD ) and liver hepatocellular carcinoma ( LIHC ), and the male‐specific protein was associated with higher mortality rate and worse overall survival in patients with LUAD and LIHC . Overexpression of TSPY 1 promotes cell proliferation, invasiveness, and cycle transition and inhibits apoptosis, whereas TSPY 1 knockdown has the opposite effects on these cancer cell phenotypes. Transcriptomic analysis revealed the involvement of TSPY 1 in PI 3K/ AKT and RAS signaling pathways in both LUAD and LIHC cells, which was further confirmed by the increase in the levels of phosphorylated proteins in the PI 3K‐ AKT and RAS signaling pathways in TSPY 1‐overexpressing cancer cells, and by the suppression on the activity of these two pathways in TSPY 1‐knockdown cells. Further investigation identified that TSPY 1 could directly bind to the promoter of insulin growth factor binding protein 3 ( IGFBP 3) to inhibit IGFBP 3 expression and that downregulation of IGFBP 3 increased the activity of PI 3K/ AKT / mTOR / BCL 2 and RAS / RAF / MEK / ERK / JUN signaling in LUAD and LIHC cells. Taken together, the observations reveal a novel mechanism by which TSPY 1 could contribute to the progression of LUAD and LIHC . Our finding is of importance for evaluating the potential of TSPY 1 in immunotherapy of male tumor patients with TSPY 1 expression.