IGSF1/Igsf1功能缺失突变导致中枢甲状腺功能减退。Igsf1基因敲除小鼠垂体促甲状腺激素释放激素受体减少,Trhr,表达式,也许有助于表型。因为甲状腺激素负调节Trhr,我们假设IGSF1可能影响垂体促甲状腺激素的甲状腺激素利用率.与这个想法一致,IGSF1在转染细胞中与甲状腺激素转运蛋白单羧酸转运蛋白8(MCT8)共免疫沉淀。这种关联与携带患者衍生突变的IGSF1受损。野生型IGSF1没有,然而,改变MCT8介导的甲状腺激素导入异源细胞。IGSF1和MCT8均在脉络丛的顶膜中表达。然而,在Igsf1敲除小鼠中,脉络丛中的MCT8蛋白水平和定位没有改变,排除IGSF1的必要陪伴功能。MCT8在垂体中的表达较低,在Igsf1敲除中同样不受影响。我们接下来评估IGSF1是否影响甲状腺激素转运或作用,通过MCT8或其他方式,在体内。为此,我们用外源性甲状腺激素治疗甲状腺功能减退野生型和Igsf1基因敲除小鼠。在两种基因型中,T4和T3抑制TSH释放并相似地调节垂体和前脑基因表达。有趣的是,垂体TSHβ亚基(Tshb)表达在Igsf1敲除中相对于野生型持续降低,无论实验条件如何,而Trhr受到的影响更大。虽然IGSF1和MCT8可以在异源细胞中相互作用,它们之间的生理相关性尚不清楚。然而,结果表明,IGSF1缺失可独立于TRHR水平或甲状腺激素作用的改变而损害TSH的产生.
Loss of function mutations in
IGSF1/
Igsf1 cause central hypothyroidism. Igsf1 knockout mice have reduced pituitary thyrotropin-releasing hormone receptor, Trhr, expression, perhaps contributing to the phenotype. Because thyroid hormones negatively regulate Trhr, we hypothesized that IGSF1 might affect thyroid hormone availability in pituitary thyrotropes. Consistent with this idea, IGSF1 coimmunoprecipitated with the thyroid hormone transporter monocarboxylate transporter 8 (MCT8) in transfected cells. This association was impaired with
IGSF1 bearing patient-derived mutations. Wild-type IGSF1 did not, however, alter MCT8-mediated thyroid hormone import into heterologous cells.
IGSF1 and MCT8 are both expressed in the apical membrane of the choroid plexus. However, MCT8 protein levels and localization in the choroid plexus were unaltered in Igsf1 knockout mice, ruling out a necessary chaperone function for
IGSF1. MCT8 expression was low in the pituitary and was similarly unaffected in
Igsf1 knockouts. We next assessed whether IGSF1 affects thyroid hormone transport or action, by MCT8 or otherwise, in vivo. To this end, we treated hypothyroid wild-type and Igsf1 knockout mice with exogenous thyroid hormones. T4 and T3 inhibited TSH release and regulated pituitary and forebrain gene expression similarly in both genotypes. Interestingly, pituitary TSH beta subunit (Tshb) expression was consistently reduced in Igsf1 knockouts relative to wild-type regardless of experimental condition, whereas Trhr was more variably affected. Although IGSF1 and MCT8 can interact in heterologous cells, the physiological relevance of their association is not clear. Nevertheless, the results suggest that IGSF1 loss can impair TSH production independently of alterations in TRHR levels or thyroid hormone action.