FBXO7 sensitivity of phenotypic traits elucidated by a hypomorphic allele

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.

FBXO7编码一种含F框的蛋白质，该蛋白可与多种伴侣蛋白相互作用，参与诸多细胞进程，并作为SCF型E3泛素连接酶复合物（SCF E3 ubiquitin ligase complex）的经典组分发挥功能。FBXO7突变可导致早发性帕金森样锥体综合征，全基因组关联研究亦证实FBXO7的基因变异与红细胞系性状相关。果蝇中存在其推定同源基因nutcracker，该基因已被证实可调控蛋白酶体，其缺失会引发雄性不育。据此，我们推测在小鼠模型中调控Fbxo7的表达水平，可为阐明该蛋白在哺乳动物体内的功能提供研究线索。我们采用了靶向基因捕获模型，该模型可保留4%至16%的残余基因表达，并以此评估表型性状对基因剂量的敏感性。Fbxo7低表达突变体小鼠表现出再生性贫血，伴随红细胞半衰期缩短，且雄性个体不育。研究同时观察到T细胞表型发生改变，有趣的是，此类改变同时兼具T细胞内在与外在调控特征。低表达突变体小鼠还对沙门氏菌感染易感，可死于通常属于亚致死剂量的感染攻击。尽管存在上述表型，Fbxo7低表达突变体小鼠仍以正常孟德尔比率出生，且寿命正常，未表现出任何神经系统症状。上述研究数据表明，红细胞存活、T细胞发育及精子发生过程对Fbxo7的基因剂量尤为敏感。