학술논문
FBXO7 sensitivity of phenotypic traits elucidated by a hypomorphic allele.
Document Type
Article
Author
Ballesteros Reviriego, Carmen; Clare, Simon; Arends, Mark J.; Cambridge, Emma L.; Swiatkowska, Agnieszka; Caetano, Susana; Abu-Helil, Bushra; Kane, Leanne; Harcourt, Katherine; Goulding, David A.; Gleeson, Diane; Ryder, Edward; Doe, Brendan; White, Jacqueline K.; van der Weyden, Louise; Dougan, Gordon; Adams, David J.; Speak, Anneliese O.
Source
Subject
*HUMAN phenotype
*ALLELES
*PROTEIN-protein interactions
*UBIQUITIN ligases
*GENETIC mutation
*PARKINSONIAN disorders
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Language
ISSN
1932-6203
Abstract
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. [ABSTRACT FROM AUTHOR]