{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\n Recent studies have revealed that C2CD6 plays a pivotal role in sperm function by contributing to calcium‐dependent signaling. In mice, C2CD6—an uncharacterized protein containing a calcium‐dependent, membrane‐targeting C2 domain—has been identified as an integral subunit of the CatSper calcium channel complex. It physically associates with the core-forming CatSper subunits as well as the pH-dependent calcium sensor EFCAB9, thereby facilitating the assembly of highly organized calcium signaling nanodomains on the flagellar membrane. Loss of C2CD6 results in depletion of these nanodomains, reduced CatSper currents, impaired sperm hyperactivation, and ultimately male sterility."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n In addition, exome sequencing studies in the context of human globozoospermia—a rare form of male infertility featuring round-headed spermatozoa with acrosomal defects—have identified rare missense mutations in C2CD6 (also known as ALS2CR11). Although its precise role in acrosome formation remains to be fully elucidated, this genetic association indicates that C2CD6 may also contribute to proper sperm morphogenesis and acrosomal development."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "2"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n Together, these findings underscore the functional importance of C2CD6 as a calcium-dependent mediator that not only ensures the proper formation and function of CatSper channel nanodomains critical for sperm hyperactivation but may also be involved in aspects of sperm head development, thereby supporting overall male fertility.\n "}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Fang Yang, Maria Gracia Gervasi, Gerardo Orta, et al. "}, {"type": "b", "children": [{"type": "t", "text": "C2CD6 regulates targeting and organization of the CatSper calcium channel complex in sperm flagella."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Development (2022)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1242/dev.199988"}], "href": "https://doi.org/10.1242/dev.199988"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "34919125"}], "href": "https://pubmed.ncbi.nlm.nih.gov/34919125"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "M S Oud, Ö Okutman, L A J Hendricks, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Exome sequencing reveals novel causes as well as new candidate genes for human globozoospermia."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Hum Reprod (2020)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1093/humrep/dez246"}], "href": "https://doi.org/10.1093/humrep/dez246"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "31985809"}], "href": "https://pubmed.ncbi.nlm.nih.gov/31985809"}]}]}]}