{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\n FLACC1 (alias ALS2CR12) is a multifunctional gene located within the 2q33 region that has emerged from several independent lines of research. Genetic association studies across multiple cancer types – including basal cell carcinoma, breast, lung, and esophageal cancers – have repeatedly implicated common variants in the CASP8/ALS2CR12 region as contributing to disease susceptibility, possibly by influencing splice variants or regulatory elements involved in apoptotic signaling (see."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": " In parallel, functional studies in the reproductive system have characterized FLACC1 as a spermatogenic cell–specific gene. In mice, alternative splicing of the Als2cr12 transcript yields an isoform that is uniquely expressed in male germ cells; the encoded protein localizes to the fibrous sheath of the sperm flagellum, suggesting an important role in sperm maturation and motility."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "3"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n Moreover, epigenetic investigations in human spermatozoa have demonstrated that alterations in DNA methylation at FLACC1/ALS2CR12 are associated with reduced fecundity and other adverse effects caused by environmental factors such as heavy tobacco smoking. In these studies, significant differences in CpG methylation and concomitant changes in gene expression were observed when comparing subfertile or heavily exposed males to controls, supporting a role for FLACC1 in maintaining normal sperm function."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "4"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n Together, the available data suggest that FLACC1/ALS2CR12 may serve dual functions: its genetic variation is linked to cancer susceptibility—likely via modulation of apoptotic pathways in concert with nearby CASP8—and its testis-specific expression and epigenetic regulation underpin essential roles in spermatogenesis and sperm function.\n "}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Simon N Stacey, Hannes Helgason, Sigurjon A Gudjonsson, et al. "}, {"type": "b", "children": [{"type": "t", "text": "New basal cell carcinoma susceptibility loci."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Nat Commun (2015)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/ncomms7825"}], "href": "https://doi.org/10.1038/ncomms7825"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "25855136"}], "href": "https://pubmed.ncbi.nlm.nih.gov/25855136"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Wei-Yu Lin, Nicola J Camp, Maya Ghoussaini, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Identification and characterization of novel associations in the CASP8/ALS2CR12 region on chromosome 2 with breast cancer risk."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Hum Mol Genet (2015)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1093/hmg/ddu431"}], "href": "https://doi.org/10.1093/hmg/ddu431"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "25168388"}], "href": "https://pubmed.ncbi.nlm.nih.gov/25168388"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Eunyoung Choi, Chunghee Cho "}, {"type": "b", "children": [{"type": "t", "text": "Expression of a sperm flagellum component encoded by the Als2cr12 gene."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Gene Expr Patterns (2011)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.gep.2011.03.003"}], "href": "https://doi.org/10.1016/j.gep.2011.03.003"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "21402173"}], "href": "https://pubmed.ncbi.nlm.nih.gov/21402173"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "M Laqqan, M E Hammadeh "}, {"type": "b", "children": [{"type": "t", "text": "Alterations in DNA methylation patterns and gene expression in spermatozoa of subfertile males."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Andrologia (2018)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1111/and.12934"}], "href": "https://doi.org/10.1111/and.12934"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "29230837"}], "href": "https://pubmed.ncbi.nlm.nih.gov/29230837"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Mohammed M Laqqan, Maged M Yassin "}, {"type": "b", "children": [{"type": "t", "text": "Cigarette heavy smoking alters DNA methylation patterns and gene transcription levels in humans spermatozoa."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Environ Sci Pollut Res Int (2022)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1007/s11356-021-17786-8"}], "href": "https://doi.org/10.1007/s11356-021-17786-8"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "34855177"}], "href": "https://pubmed.ncbi.nlm.nih.gov/34855177"}]}]}]}