FBXO7 sensitivity of phenotypic traits elucidated by a hypomorphic allele

Carmen Ballesteros Reviriego, Simon Clare, Mark Arends, Emma L Cambridge, Agnieszka Swiatkowska, Susana Caetano, Bushra Abu-Helil, Leanne Kane, Katherine Harcourt, David Goulding, Diane Gleeson, Edward Ryder, Brendan Doe, Jacqueline K White, Louise van der Weyden, Gordon Dougan, David J Adams, Anneliese O Speak

Research output: Contribution to journalArticlepeer-review


FBXO7 encodes an F box containing protein that interacts with multiple partners to facilitate numerous cellular processes and has a canonical role as part of an SCF E3 ubiquitin ligase complex. Mutation of FBXO7 is responsible for an early onset Parkinsonian pyramidal syndrome and genome-wide association studies have linked variants in FBXO7 to erythroid traits. A putative orthologue in Drosophila, nutcracker, has been shown to regulate the proteasome, and deficiency of nutcracker results in male infertility. Therefore, we reasoned that modulating Fbxo7 levels in a murine model could provide insights into the role of this protein in mammals. We used a targeted gene trap model which retained 4 - 16 % residual gene expression and assessed the sensitivity of phenotypic traits to gene dosage. Fbxo7 hypomorphs showed regenerative anaemia associated with a shorter erythrocyte half-life, and male mice were infertile. Alterations to T cell phenotypes were also observed, which intriguingly were both T cell intrinsic and extrinsic. Hypomorphic mice were also sensitive to infection with Salmonella, succumbing to a normally sublethal challenge. Despite these phenotypes, Fbxo7 hypomorphs were produced at a normal Mendelian ratio with a normal lifespan and no evidence of neurological symptoms. These data suggest that erythrocyte survival, T cell development and spermatogenesis are particularly sensitive to Fbxo7 gene dosage.
Original languageEnglish
JournalPLoS ONE
Issue number3
Publication statusPublished - 6 Mar 2019


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