Copy number variation of two separate regulatory regions upstream of SOX9 causes isolated 46,XY or 46,XX disorder of sex development
Copy number variation of two separate regulatory regions upstream of SOX9 causes isolated 46,XY or 46,XX disorder of sex development
复制标题
DOI：
10.1136/jmedgenet-2014-102864
复制
发表时间：
2015-04-01
影响因子：
4
通讯作者：
Scherer, Gerd
中科院分区：
文献类型：
--
作者：
Kim, Gwang-Jin;Sock, Elisabeth;Scherer, Gerd
背景：SOX 9基因突变导致骨骼畸形综合征，伴XY性反转。在小鼠中的研究表明，SOX 9作为SRY下游的睾丸诱导转录因子，触发支持细胞和睾丸分化。Sox 9的SRY依赖性睾丸特异性增强子仅在小鼠中被鉴定。先前的研究表明，SOX 9上游517-595 kb的78 kb区域的拷贝数变异（CNVs）与46，XY和46，XX性发育障碍（DSD）的病因有关。结果通过CNV分析，我们在3例SRY阴性的46，XX DSD患者中发现了SOX 9基因上游的重复序列，这与先前报道的重复序列一起定义了SOX 9基因上游516-584 kb的68 kb区域，命名为XXSR（XX sex reversal region）。更重要的是，我们在4个SRY阳性的46，XY DSD无骨骼表型的家庭中鉴定了杂合缺失，其定义了SOX 9上游607.1-639.6 kb的32.5 kb间隔，称为XY性逆转区（XYSR）。为了定位可疑的睾丸特异性增强子，在细胞转染和转基因实验中测试XYSR亚片段。虽然转基因实验仍不确定，一个1.9 kb SRY响应的亚片段驱动的表达，特别是在Sertoli样cells.Conclusions我们的研究结果表明，分离的46，XY和46，XX DSD可以分配到两个独立的监管区域，XYSR和XXSR，远在上游的SOX 9。来自XYSR的1.9 kb SRY响应亚片段可能构成了人SOX 9支持细胞增强子的核心，代表了迄今为止在男性性别决定的遗传级联中缺失的一环。
Background SOX9 mutations cause the skeletal malformation syndrome campomelic dysplasia in combination with XY sex reversal. Studies in mice indicate that SOX9 acts as a testis-inducing transcription factor downstream of SRY, triggering Sertoli cell and testis differentiation. An SRY-dependent testis-specific enhancer for Sox9 has been identified only in mice. A previous study has implicated copy number variations (CNVs) of a 78 kb region 517-595 kb upstream of SOX9 in the aetiology of both 46,XY and 46,XX disorders of sex development (DSD). We wanted to better define this region for both disorders.Results By CNV analysis, we identified SOX9 upstream duplications in three cases of SRY-negative 46,XX DSD, which together with previously reported duplications define a 68 kb region, 516-584 kb upstream of SOX9, designated XXSR (XX sex reversal region). More importantly, we identified heterozygous deletions in four families with SRY-positive 46,XY DSD without skeletal phenotype, which define a 32.5 kb interval 607.1-639.6 kb upstream of SOX9, designated XY sex reversal region (XYSR). To localise the suspected testis-specific enhancer, XYSR subfragments were tested in cell transfection and transgenic experiments. While transgenic experiments remained inconclusive, a 1.9 kb SRY-responsive subfragment drove expression specifically in Sertoli-like cells.Conclusions Our results indicate that isolated 46, XY and 46, XX DSD can be assigned to two separate regulatory regions, XYSR and XXSR, far upstream of SOX9. The 1.9 kb SRY-responsive subfragment from the XYSR might constitute the core of the Sertoli-cell enhancer of human SOX9, representing the so far missing link in the genetic cascade of male sex determination.