In mice, male sex determination depends on FGF9 signalling via FGFR2c in the bipotential gonads to maintain the expression of the key testis gene SOX9. In humans, however, while FGFR2 mutations have been linked to 46,XY disorders of sex development (DSD), the role of FGF9 is unresolved. The only reported pathogenic mutations in human FGF9, FGF9^S99N and FGF9^R62G, are dominant and result in craniosynostosis (fusion of cranial sutures) or multiple synostoses (fusion of limb joints). Whether these synostosis-causing FGF9 mutations impact upon gonadal development and DSD etiology has not been explored. We therefore examined embryonic gonads in the well-characterized Fgf9 missense mouse mutants, Fgf9^S99N and Fgf9^N143T, which phenocopy the skeletal defects of FGF9^S99N and FGF9^R62G variants, respectively. XY Fgf9^S99N/S99N and XY Fgf9^N143T/N143T fetal mouse gonads showed severely disorganized testis cords and partial XY sex reversal at 12.5 days post coitum (dpc), suggesting loss of FGF9 function. By 15.5 dpc, testis development in both mutants had partly recovered. Mitotic analysis in vivo and in vitro suggested that the testicular phenotypes in these mutants arise in part through reduced proliferation of the gonadal supporting cells. These data raise the possibility that human FGF9 mutations causative for dominant skeletal conditions can also lead to loss of FGF9 function in the developing testis, at least in mice. Our data suggest that, in humans, testis development is largely tolerant of deleterious FGF9 mutations which lead to skeletal defects, thus offering an explanation as to why XY DSDs are rare in patients with pathogenic FGF9 variants.

中文翻译：

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FGF9 小鼠人类关节综合征模型中性发育的卵睾疾病。

在小鼠中，男性性别决定依赖于 FGF9 信号通过双能性腺中的 FGFR2c 来维持关键睾丸基因SOX9的表达。然而，在人类中，虽然FGFR2突变与 46,XY 性发育障碍 (DSD) 相关，但 FGF9 的作用尚未解决。人类FGF9、FGF9 ^S99N和FGF9 ^{R62G 中}唯一报道的致病突变是显性的，并导致颅缝早闭（颅缝融合）或多发性合缝（四肢关节融合）。是否这些导致关节粘连的FGF9尚未探讨突变对性腺发育和 DSD 病因的影响。因此，我们检查了充分表征的Fgf9错义小鼠突变体Fgf9 ^S99N和Fgf9 ^N143T中的胚胎性腺，它们分别模拟了FGF9 ^S99N和FGF9 ^R62G变体的骨骼缺陷。XY Fgf9 ^S99N/S99N和 XY Fgf9 ^N143T/N143T胎鼠性腺在性交后 12.5 天 (dpc) 表现出严重紊乱的睾丸索和部分 XY 性别逆转，表明 FGF9 功能丧失。到 15.5 dpc，两个突变体的睾丸发育已部分恢复。有丝分裂分析体内和体外表明这些突变体中的睾丸表型部分是通过减少性腺支持细胞的增殖而产生的。这些数据增加了导致显性骨骼疾病的人类FGF9突变也可能导致发育中睾丸中 FGF9 功能丧失的可能性，至少在小鼠中是这样。我们的数据表明，在人类中，睾丸发育在很大程度上耐受导致骨骼缺陷的有害FGF9突变，从而解释了为什么 XY DSD 在具有致病性FGF9变异的患者中很少见。