Brûlé Emilie, Heinen Charlotte A, Smith Courtney L, Schang Gauthier, Li Yining, Zhou Xiang, Wang Ying, Joustra Sjoerd D, Wit Jan M, Fliers Eric, Repping Sjoerd, van Trotsenburg A S Paul, Bernard Daniel J
Department of Anatomy and Cell Biology, McGill University, Montréal, Québec H3A 0C7, Canada.
Emma Children's Hospital, Amsterdam University Medical Centers, University of Amsterdam, Department of Pediatric Endocrinology, 1105 Amsterdam, the Netherlands.
J Endocr Soc. 2021 Feb 20;5(4):bvab023. doi: 10.1210/jendso/bvab023. eCollection 2021 Apr 1.
Loss-of-function mutations in the X-linked immunoglobulin superfamily, member 1 () gene result in central hypothyroidism, often associated with macroorchidism. Testicular enlargement in these patients might be caused by increases in follicle-stimulating hormone (FSH) levels, as IGSF1 has been proposed to function as an inhibin B receptor or as an inhibitor of activin type I receptor (ALK4) activity in pituitary gonadotrope cells. If true, loss of IGSF1 should lead to reduced inhibin B action or disinhibition of activin signaling, thereby increasing FSH synthesis. Here, we show that FSH levels and sperm counts are normal in male knockout mice, although testis size is mildly increased. Sperm parameters are also normal in men with IGSF1 deficiency, although their FSH levels may trend higher and their testes are enlarged. Inhibin B retains the ability to suppress FSH synthesis in pituitaries of -knockout mice and IGSF1 does not interact with ALK4 or alter activin A/ALK4 stimulation of FSHβ () subunit transcription or expression. In light of these results, it is unlikely that macroorchidism in IGSF1 deficiency derives from alterations in spermatogenesis or inhibin/activin regulation of FSH.
X连锁免疫球蛋白超家族成员1（IGSF1）基因的功能丧失突变会导致中枢性甲状腺功能减退，常伴有巨睾症。这些患者的睾丸增大可能是由促卵泡激素（FSH）水平升高引起的，因为有人提出IGSF1在垂体促性腺激素细胞中作为抑制素B受体或作为I型激活素受体（ALK4）活性的抑制剂发挥作用。如果这是真的，IGSF1的缺失应该会导致抑制素B作用减弱或激活素信号的去抑制，从而增加FSH的合成。在这里，我们表明，雄性IGSF1基因敲除小鼠的FSH水平和精子数量正常，尽管睾丸大小略有增加。IGSF1缺乏的男性精子参数也正常，尽管他们的FSH水平可能略高且睾丸增大。抑制素B在IGSF1基因敲除小鼠的垂体中仍保留抑制FSH合成的能力，并且IGSF1不与ALK4相互作用，也不改变激活素A/ALK4对FSHβ亚基转录或表达的刺激。鉴于这些结果，IGSF1缺乏导致的巨睾症不太可能源于精子发生的改变或抑制素/激活素对FSH的调节。
