Mutations in LRRC50 predispose zebrafish and humans to seminomas

Sander G Basten, Erica E Davis, Ad J M Gillis, Ellen van Rooijen, Hans Stoop, Nikolina Babala, Ive Logister, Zachary G Heath, Trudy N Jonges, Nicholas Katsanis, Emile E Voest, Freek J van Eeden, Rene H Medema, René F Ketting, Stefan Schulte-Merker, Leendert H J Looijenga, Rachel H Giles

Onderzoeksoutput: Bijdrage aan tijdschriftArtikelpeer review

Samenvatting

Seminoma is a subclass of human testicular germ cell tumors (TGCT), the most frequently observed cancer in young men with a rising incidence. Here we describe the identification of a novel gene predisposing specifically to seminoma formation in a vertebrate model organism. Zebrafish carrying a heterozygous nonsense mutation in Leucine-Rich Repeat Containing protein 50 (lrrc50 also called dnaaf1), associated previously with ciliary function, are found to be highly susceptible to the formation of seminomas. Genotyping of these zebrafish tumors shows loss of heterozygosity (LOH) of the wild-type lrrc50 allele in 44.4% of tumor samples, correlating with tumor progression. In humans we identified heterozygous germline LRRC50 mutations in two different pedigrees with a family history of seminomas, resulting in a nonsense Arg488* change and a missense Thr590Met change, which show reduced expression of the wild-type allele in seminomas. Zebrafish in vivo complementation studies indicate the Thr590Met to be a loss-of-function mutation. Moreover, we show that a pathogenic Gln307Glu change is significantly enriched in individuals with seminoma tumors (13% of our cohort). Together, our study introduces an animal model for seminoma and suggests LRRC50 to be a novel tumor suppressor implicated in human seminoma pathogenesis.

Originele taal-2Engels
Pagina's (van-tot)e1003384
TijdschriftPLoS genetics
Volume9
Nummer van het tijdschrift4
DOI's
StatusGepubliceerd - apr. 2013
Extern gepubliceerdJa

Vingerafdruk

Duik in de onderzoeksthema's van 'Mutations in LRRC50 predispose zebrafish and humans to seminomas'. Samen vormen ze een unieke vingerafdruk.

Citeer dit