Human cyritestin genes (CYRN1 and CYRN2) are non-functional

Abstract

The mouse cyritestin gene is a member of the ADAM (a disintegrin and metalloprotease) gene family and codes for a membrane-anchored sperm protein. Recently, it was shown that cyritestin is critical for male fertility in the mouse. Spermatozoa of cyritestin-deficient mice are not able to bind to the zona pellucida of the oocyte and therefore unable to fertilize the egg. However, zona-free oocytes can be fertilized and the resulting embryos show normal development. In contrast to the mouse, where only one gene for cyritestin (Cyrn) is reported, two cyritestin genes (CYRN1 and CYRN2) are known in humans. The human CYRN1 and CYRN2 genes are located on chromosomes 8 and 16, respectively. We report that 27% of fertile men are deficient for the CYRN1 gene but that all have a CYRN2 gene, suggesting that the CYRN2 gene is the orthologous mouse cyritestin gene in humans and might be involved in sperm-egg interactions. However, the characterization of CYRN2 transcripts from testicular RNA of CYRN1-deficient men demonstrated many termination codons in the synthesized cyritestin cDNA. Furthermore, Western-blot analysis with human testicular protein extracts using an anti-cyritestin antibody failed to detect any cyritestin protein. These results demonstrate clearly that both cyritestin genes are non-functional in humans.

The mechanism of sperm–egg interaction and the involvement of IZUMO1 in fusion

“…19,23,24,[36][37][38] This indicates that ADAM3 is the key molecule in fertilization, but this scheme is not applicable in human because Adam3 is a pseudogene in human. 62 Thus, although a partial mechanism has been clarified, a new (or modified) outline for the mechanism of fertilization must await the results of further gene knockout experiments. Concerning fusion mechanism, it might be important to broaden our focus to wider areas of the cell-cell fusion process such as the formation of myotubes, placenta, multinucleated osteoclasts and macrophages, for example.…”

The cell biology of mammalian fertilization

“…If ADAM3 became aberrant, spermatozoa could not migrate into the oviduct and hence failed to approach eggs. However, ADAM3 is a pseudogene in human (Grzmil et al, 2001). Therefore, if a general mechanism does exist among mammalian species, we might still not have found the key factor for fertilization.…”

Fertilization: a sperm’s journey to and interaction with the oocyte

“…These observations point toward Adam3 as the most important factor that participates in sperm-ZP binding. However, in humans, other ADAMs, or another protein, are likely to function as an alternative to Adam3, because the human homolog of Adam3 seems to be a pseudo gene (98,99). In fact, there are various papers showing that other proteins are involved in human sperm binding to the ZP, including the 56-kDa Zp3 receptor (ZP3R) and zonadhesin (ZAN).…”