{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,5]],"date-time":"2026-06-05T03:47:22Z","timestamp":1780631242793,"version":"3.54.1"},"reference-count":65,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2024,1,30]],"date-time":"2024-01-30T00:00:00Z","timestamp":1706572800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100002428","name":"Austrian Research Fund (FWF)","doi-asserted-by":"publisher","award":["P30867000"],"award-info":[{"award-number":["P30867000"]}],"id":[{"id":"10.13039\/501100002428","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002428","name":"Austrian Research Fund (FWF)","doi-asserted-by":"publisher","award":["FWFP25525000-"],"award-info":[{"award-number":["FWFP25525000-"]}],"id":[{"id":"10.13039\/501100002428","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002428","name":"Austrian Research Fund (FWF)","doi-asserted-by":"publisher","award":["SFB F-8809-B"],"award-info":[{"award-number":["SFB F-8809-B"]}],"id":[{"id":"10.13039\/501100002428","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Johannes Kepler University","award":["P30867000"],"award-info":[{"award-number":["P30867000"]}]},{"name":"Johannes Kepler University","award":["FWFP25525000-"],"award-info":[{"award-number":["FWFP25525000-"]}]},{"name":"Johannes Kepler University","award":["SFB F-8809-B"],"award-info":[{"award-number":["SFB F-8809-B"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>Advanced paternal age increases the risk of transmitting de novo germline mutations, particularly missense mutations activating the receptor tyrosine kinase (RTK) signalling pathway, as exemplified by the FGFR3 mutation, which is linked to achondroplasia (ACH). This risk is attributed to the expansion of spermatogonial stem cells carrying the mutation, forming sub-clonal clusters in the ageing testis, thereby increasing the frequency of mutant sperm and the number of affected offspring from older fathers. While prior studies proposed a correlation between sub-clonal cluster expansion in the testis and elevated mutant sperm production in older donors, limited data exist on the universality of this phenomenon. Our study addresses this gap by examining the testis-expansion patterns, as well as the increases in mutations in sperm for two FGFR3 variants\u2014c.1138G&gt;A (p.G380R) and c.1948A&gt;G (p.K650E)\u2014which are associated with ACH or thanatophoric dysplasia (TDII), respectively. Unlike the ACH mutation, which showed sub-clonal expansion events in an aged testis and a significant increase in mutant sperm with the donor\u2019s age, as also reported in other studies, the TDII mutation showed focal mutation pockets in the testis but exhibited reduced transmission into sperm and no significant age-related increase. The mechanism behind this divergence remains unclear, suggesting potential pleiotropic effects of aberrant RTK signalling in the male germline, possibly hindering differentiation requiring meiosis. This study provides further insights into the transmission risks of micro-mosaics associated with advanced paternal age in the male germline.<\/jats:p>","DOI":"10.3390\/genes15020191","type":"journal-article","created":{"date-parts":[[2024,1,30]],"date-time":"2024-01-30T11:35:34Z","timestamp":1706614534000},"page":"191","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Exploring the Micro-Mosaic Landscape of FGFR3 Mutations in the Ageing Male Germline and Their Potential Implications in Meiotic Differentiation"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2191-9783","authenticated-orcid":false,"given":"Yasmin","family":"Striedner","sequence":"first","affiliation":[{"name":"Institute of Biophysics, Johannes Kepler University, 4020 Linz, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8367-1560","authenticated-orcid":false,"given":"Barbara","family":"Arbeithuber","sequence":"additional","affiliation":[{"name":"Institute of Biophysics, Johannes Kepler University, 4020 Linz, Austria"},{"name":"Department of Gynecology, Obstetrics and Gynecological Endocrinology, Johannes Kepler University, 4020 Linz, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9000-2290","authenticated-orcid":false,"given":"Sofia","family":"Moura","sequence":"additional","affiliation":[{"name":"Institute of Biophysics, Johannes Kepler University, 4020 Linz, Austria"},{"name":"John P. Hussman Institute for Human Genomics, Miller School of Medicine, University of Miami, Miami, FL 33136, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elisabeth","family":"Nowak","sequence":"additional","affiliation":[{"name":"Institute of Biophysics, Johannes Kepler University, 4020 Linz, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ronja","family":"Reinhardt","sequence":"additional","affiliation":[{"name":"Institute of Biophysics, Johannes Kepler University, 4020 Linz, Austria"},{"name":"Department of Structural and Computational Biology, Max Perutz Labs, Campus Vienna Biocenter 5, 1030 Vienna, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leila","family":"Muresan","sequence":"additional","affiliation":[{"name":"Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge CB2 2EL, UK"},{"name":"Faculty of Science and Engineering, Anglia Ruskin University, Cambridge CB1 1PT, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8436-9304","authenticated-orcid":false,"given":"Renato","family":"Salazar","sequence":"additional","affiliation":[{"name":"Institute of Biophysics, Johannes Kepler University, 4020 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\/0000-0002-3621-7020","authenticated-orcid":false,"given":"Irene","family":"Tiemann-Boege","sequence":"additional","affiliation":[{"name":"Institute of Biophysics, Johannes Kepler University, 4020 Linz, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,1,30]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2109","DOI":"10.1056\/NEJMoa1616288","article-title":"Tracking the Evolution of Non-Small-Cell Lung Cancer","volume":"376","author":"Wilson","year":"2017","journal-title":"N. 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