Copy number variation in patients with disorders of sex development due to 46,XY gonadal dysgenesis.
Copy number variation in patients with disorders of sex development due to 46,XY gonadal dysgenesis.
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DOI：
10.1371/journal.pone.0017793
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发表时间：
2011-03-07
期刊：
影响因子：
3.7
通讯作者：
Sinclair A
中科院分区：
文献类型：
--
作者：
White S;Ohnesorg T;Notini A;Roeszler K;Hewitt J;Daggag H;Smith C;Turbitt E;Gustin S;van den Bergen J;Miles D;Western P;Arboleda V;Schumacher V;Gordon L;Bell K;Bengtsson H;Speed T;Hutson J;Warne G;Harley V;Koopman P;Vilain E;Sinclair A
性发育障碍（DSD）的严重程度从轻微的生殖器异常到完全的性逆转，是患者及其家属关注的主要问题。DSD通常是由于调节性腺发育的遗传程序的破坏。尽管在这些发育途径中已经发现了一些基因，但在超过50%的46，xy DSD病例中尚未发现致病突变。我们使用Affymetrix全基因组人类SNP阵列6.0分析了23例由于性腺发育不良（GD）而患有不明原因的46，xy DSD的个体的拷贝数变异。这里我们描述了可能导致GD的拷贝数的三个离散变化。首先，我们在X染色体上发现了一个包含DAX1 （NR0B1）的大重复。其次，我们发现了一个重排，似乎影响了已知睾丸基因SOX9中一个新的性腺特异性调节区域。令人惊讶的是，该患者没有任何镰状体发育不良的迹象，这表明缺失仅影响性腺中SOX9的表达。对该缺失区域内潜在SRY结合位点的功能分析确定了5个假定的增强子，这表明已知SRY结合TES增强子之外的序列影响人类睾丸特异性SOX9的表达。第三，我们确定了GATA4下游的一个小缺失，支持GATA4在人类性腺发育中的作用。这些CNV分析为人类性腺发育和功能障碍的通路提供了新的见解，并表明干扰基因调控的非编码序列重排可能占DSD病例的很大比例。
Disorders of sex development (DSD), ranging in severity from mild genital abnormalities to complete sex reversal, represent a major concern for patients and their families. DSD are often due to disruption of the genetic programs that regulate gonad development. Although some genes have been identified in these developmental pathways, the causative mutations have not been identified in more than 50% 46,XY DSD cases. We used the Affymetrix Genome-Wide Human SNP Array 6.0 to analyse copy number variation in 23 individuals with unexplained 46,XY DSD due to gonadal dysgenesis (GD). Here we describe three discrete changes in copy number that are the likely cause of the GD. Firstly, we identified a large duplication on the X chromosome that included DAX1 (NR0B1). Secondly, we identified a rearrangement that appears to affect a novel gonad-specific regulatory region in a known testis gene, SOX9. Surprisingly this patient lacked any signs of campomelic dysplasia, suggesting that the deletion affected expression of SOX9 only in the gonad. Functional analysis of potential SRY binding sites within this deleted region identified five putative enhancers, suggesting that sequences additional to the known SRY-binding TES enhancer influence human testis-specific SOX9 expression. Thirdly, we identified a small deletion immediately downstream of GATA4, supporting a role for GATA4 in gonad development in humans. These CNV analyses give new insights into the pathways involved in human gonad development and dysfunction, and suggest that rearrangements of non-coding sequences disturbing gene regulation may account for significant proportion of DSD cases.
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影响因子：
64.8
作者：
Heintzman, Nathaniel D.;Hon, Gary C.;Hawkins, R. David;Kheradpour, Pouya;Stark, Alexander;Harp, Lindsey F.;Ye, Zhen;Lee, Leonard K.;Stuart, Rhona K.;Ching, Christina W.;Ching, Keith A.;Antosiewicz-Bourget, Jessica E.;Liu, Hui;Zhang, Xinmin;Green, Roland D.;Lobanenkov, Victor V.;Stewart, Ron;Thomson, James A.;Crawford, Gregory E.;Kellis, Manolis;Ren, Bing
通讯作者：
Ren, Bing
影响因子：
3.5
作者：
Barbaro, M.;Cicognani, A.;Oscarson, M.
通讯作者：
Oscarson, M.
影响因子：
4.4
作者：
Bagheri-Fam, S;Ferraz, C;Pfeifer, D
通讯作者：
Pfeifer, D
影响因子：
30.8
作者：
Iafrate, AJ;Feuk, L;Lee, C
通讯作者：
Lee, C
影响因子：
6.1
作者：
Ledig, S.;Hiort, O.;Wieacker, P.
通讯作者：
Wieacker, P.