Mitsuhashi Tomoko, Warita Katsuhiko, Sugawara Teruo, Tabuchi Yoshiaki, Takasaki Ichiro, Kondo Takashi, Hayashi Fumio, Wang Zhi-Yu, Matsumoto Yoshiki, Miki Takanori, Takeuchi Yoshiki, Ebina Yasuhiko, Yamada Hideto, Sakuragi Noriaki, Yokoyama Toshifumi, Nanmori Takashi, Kitagawa Hiroshi, Kant Jeffrey A, Hoshi Nobuhiko
Department of Animal Science, Graduate School of Agricultural Science, Kobe University, Kobe, Japan.
Congenit Anom (Kyoto). 2010 Jun;50(2):85-94. doi: 10.1111/j.1741-4520.2010.00274.x. Epub 2010 Feb 22.
In normal ontogenetic development, the expression of the sex-determining region of the Y chromosome (SRY) gene, involved in the first step of male sex differentiation, is spatiotemporally regulated in an elaborate fashion. SRY is expressed in germ cells and Sertoli cells in adult testes. However, only few reports have focused on the expressions of SRY and the other sex-determining genes in both the classical organ developing through these genes (gonad) and the peripheral tissue (skin) of adult XY females. In this study, we examined the gonadal tissue and fibroblasts of a 17-year-old woman suspected of having disorders of sexual differentiation by cytogenetic, histological, and molecular analyses. The patient was found to have the 46,X,inv(Y)(p11.2q11.2) karyotype and streak gonads with abnormally prolonged SRY expression. The sex-determining gene expressions in the patient-derived fibroblasts were significantly changed relative to those from a normal male. Further, the acetylated histone H3 levels in the SRY region were significantly high relative to those of the normal male. As SRY is epistatic in the sex-determination pathway, the prolonged SRY expression possibly induced a destabilizing effect on the expressions of the downstream sex-determining genes. Collectively, alterations in the sex-determining gene expressions persisted in association with disorders of sexual differentiation not only in the streak gonads but also in the skin of the patient. The findings suggest that correct regulation of SRY expression is crucial for normal male sex differentiation, even if SRY is translated normally.
在正常的个体发育过程中，参与男性性别分化第一步的Y染色体性别决定区（SRY）基因的表达，以一种精细的方式在时空上受到调控。SRY在成年睾丸的生殖细胞和支持细胞中表达。然而，仅有少数报道关注SRY及其他性别决定基因在通过这些基因发育的经典器官（性腺）和成年XY女性外周组织（皮肤）中的表达。在本研究中，我们通过细胞遗传学、组织学和分子分析，检查了一名疑似患有性分化障碍的17岁女性的性腺组织和成纤维细胞。发现该患者具有46,X,inv(Y)(p11.2q11.2)核型和条索状性腺，且SRY表达异常延长。与正常男性来源的成纤维细胞相比，患者来源的成纤维细胞中的性别决定基因表达有显著变化。此外，SRY区域的组蛋白H3乙酰化水平相对于正常男性显著升高。由于SRY在性别决定途径中具有上位性，SRY表达的延长可能对下游性别决定基因的表达产生不稳定作用。总体而言，性别决定基因表达的改变不仅在条索状性腺中，而且在患者的皮肤中持续存在，并与性分化障碍相关。这些发现表明，即使SRY正常翻译，正确调控SRY表达对于正常男性性别分化至关重要。
