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FBXO7 sensitivity of phenotypic traits elucidated by a hypomorphic allele.

Carmen Ballesteros Reviriego | Simon Clare | Mark J Arends | Emma L Cambridge | Agnieszka Swiatkowska | Susana Caetano | Bushra Abu-Helil | Leanne Kane | Katherine Harcourt | David A Goulding | Diane Gleeson | Edward Ryder | Brendan Doe | Jacqueline K White | Louise van der Weyden | Gordon Dougan | David J Adams | Anneliese O Speak
PloS one | 2019

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.

Pubmed ID: 30840666

Associated grants

  • Agency: Wellcome Trust, United Kingdom
    Id: WT098051
  • Agency: Cancer Research UK, United Kingdom

Publication data is provided by the National Library of Medicine ® and PubMed ®. Data is retrieved from PubMed ® on a weekly schedule. For terms and conditions see the National Library of Medicine Terms and Conditions.

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