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In particular, some FGFR3 mutations increase in frequency with age, but there are still a large number of uncharacterized FGFR3 mutations that could be expanding in the male germline with potentially early- or late-onset effects in the offspring. Here, we used digital polymerase chain reaction to assess the frequency and spatial distribution of 10 different FGFR3 missense substitutions in the sexually mature male germline. Our functional assessment of the receptor signaling of the variants with biophysical methods showed that 9 of these variants resulted in a higher activation of the receptor\u00b4s downstream signaling, resulting in 2 different expansion behaviors. Variants that form larger subclonal expansions in a dissected postmortem testis also showed a positive correlation of the substitution frequency with the sperm donor's age, and a high and ligand-independent FGFR3 activation. In contrast, variants that measured high FGFR3 signaling and elevated substitution frequencies independent of the donor's age did not result in measurable subclonal expansions in the testis. This suggests that promiscuous signal activation might also result in an accumulation of mutations before the sexual maturation of the male gonad with clones staying relatively constant in size throughout time. Collectively, these results provide novel insights into our understanding of the mutagenesis of driver mutations and their resulting mosaicism in the male germline with important consequences for the transmission and recurrence of associated disorders.<\/jats:p>","DOI":"10.1093\/gbe\/evae015","type":"journal-article","created":{"date-parts":[[2024,2,27]],"date-time":"2024-02-27T13:43:49Z","timestamp":1709041429000},"source":"Crossref","is-referenced-by-count":5,"title":["Exploring <i>FGFR3<\/i> Mutations in the Male Germline: Implications for Clonal Germline Expansions and Paternal Age-Related Dysplasias"],"prefix":"10.1093","volume":"16","author":[{"given":"Sofia","family":"Moura","sequence":"first","affiliation":[{"name":"Institute of Biophysics, Johannes Kepler University , Linz , Austria"},{"name":"John P. Hussman Institute for Human Genomics, Miller School of Medicine, University of Miami, Miami , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ingrid","family":"Hartl","sequence":"additional","affiliation":[{"name":"Institute of Biophysics, Johannes Kepler University , Linz , Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Veronika","family":"Brumovska","sequence":"additional","affiliation":[{"name":"Institute of Applied Physics, TU Wien , Vienna , Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter P","family":"Calabrese","sequence":"additional","affiliation":[{"name":"Quantitative and Computational Biology, University of Southern California , Los Angeles , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Atena","family":"Yasari","sequence":"additional","affiliation":[{"name":"Institute of Biophysics, Johannes Kepler University , Linz , Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2191-9783","authenticated-orcid":false,"given":"Yasmin","family":"Striedner","sequence":"additional","affiliation":[{"name":"Institute of Biophysics, Johannes Kepler University , Linz , Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5776-5993","authenticated-orcid":false,"given":"Marina","family":"Bishara","sequence":"additional","affiliation":[{"name":"Institute of Applied Physics, TU Wien , Vienna , Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Theresa","family":"Mair","sequence":"additional","affiliation":[{"name":"Institute of Biophysics, Johannes Kepler University , Linz , Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas","family":"Ebner","sequence":"additional","affiliation":[{"name":"Department of Gynecology, Obstetrics and Gynecological Endocrinology, Johannes Kepler University , 4020 Linz , Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1542-1089","authenticated-orcid":false,"given":"Gerhard J","family":"Sch\u00fctz","sequence":"additional","affiliation":[{"name":"Institute of Applied Physics, TU Wien , Vienna , Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eva","family":"Sevcsik","sequence":"additional","affiliation":[{"name":"Institute of Applied Physics, TU Wien , Vienna , Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3621-7020","authenticated-orcid":false,"given":"Irene","family":"Tiemann-Boege","sequence":"additional","affiliation":[{"name":"Institute of Biophysics, Johannes Kepler University , Linz , 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