Characterization of activating mutations in FGRF3 and their expansion in the male germline
Sprache des Vortragstitels:
Englisch
Original Tagungtitel:
Österreichische Gesselschaft für Humangenetik
Sprache des Tagungstitel:
Englisch
Original Kurzfassung:
FGFR3, is a well-known oncogene that is highly expressed in the male gonad. Here we investigated
how a series of missense mutations in FGFR3, associated with different dysplasias, expand in the male
germline. Specifically, we investigated the functional activation, as well as the occurrence in human
testis and sperm of ten different FGFR3 variants categorized by ClinVar as deleterious, benign, or not
reported. We found that FGFR3 promiscuous (ligand-independent) activation likely leads to the
accumulation of mutations in the male germline. We also observed that variants forming larger clonal
expansions in the testis also increase in frequency with age in sperm. This has important implications
of a higher transmission with paternal age, adding to the list of canonical paternal-age disorders.
However, some variants were already enriched in sperm of younger donors, and did not result in large
sub-clonal expansion events in the aging testis. This suggests that some mutation clusters might stay
constant throughout the gonad?s lifetime, a novel finding for this type of mutagenesis. Finally, we
describe three variants not reported in ClinVar that have an activating effect at the cellular level that
also could have early- or late-onset consequences in offspring. These results provide important data
for the evaluation and interpretation of variants with relevant clinical implications and the likelihood
of these variants to form micro-mosaics in the male gonad.
Sprache der Kurzfassung:
Englisch
Vortragstyp:
Hauptvortrag / Eingeladener Vortrag auf einer Tagung
Forschungs-