A recurrent p.Arg92Trp variant in steroidogenic factor-1 (NR5A1) can act as a molecular switch in human sex development.
A recurrent p.Arg92Trp variant in steroidogenic factor-1 (NR5A1) can act as a molecular switch in human sex development.
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DOI：
10.1093/hmg/ddw390
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发表时间：
2016-12-01
影响因子：
3.5
通讯作者：
Achermann JC
中科院分区：
文献类型：
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作者：
Bashamboo A;Donohoue PA;Vilain E;Rojo S;Calvel P;Seneviratne SN;Buonocore F;Barseghyan H;Bingham N;Rosenfeld JA;Mulukutla SN;Jain M;Burrage L;Dhar S;Balasubramanyam A;Lee B;Members of UDN;Dumargne MC;Eozenou C;Suntharalingham JP;de Silva K;Lin L;Bignon-Topalovic J;Poulat F;Lagos CF;McElreavey K;Achermann JC
早期人类性腺的细胞谱系致力于两种相互对立的器官发生命运之一：睾丸或卵巢。由于存在睾丸决定基因 SRY，一些具有 46,XX 核型的个体会发育睾丸或卵睾（睾丸或卵睾性发育障碍；TDSD/OTDSD）。其他罕见的复杂综合征形式的 TDSD/OTDSD 与抑制睾丸发育的促卵巢基因突变有关（例如 WNT4）；然而，更常见的非综合征形式的遗传原因尚不清楚。类固醇生成因子 1（称为 NR5A1）是生殖发育和功能的关键调节因子。 46,XY 个体中 NR5A1 功能丧失的变化与人类一系列表型相关，从缺乏睾丸形成到男性不育。 46,XX 女性中的 NR5A1 突变与原发性卵巢功能不全有关，包括卵巢形成不足、原发性和继发性闭经以及提前绝经。在这里，我们表明，NR5A1 辅助 DNA 结合区中的特定复发杂合错义突变 (p.Arg92Trp) 与来自四个不相关家庭的 46,XX 儿童和成人的不同程度的睾丸发育相关。值得注意的是，在一个家庭中，一名作为女孩长大并携带这种 NR5A1 突变的兄弟姐妹被发现具有 46,XY 核型，并伴有部分睾丸发育不全。这些独特的发现强调了发育转录因子中的特定变体如何将哺乳动物的器官命运从卵巢转变为睾丸，并且代表了第一个导致人类分离的非综合征性 46,XX 睾丸/卵睾 DSD 的错义突变。
Cell lineages of the early human gonad commit to one of the two mutually antagonistic organogenetic fates, the testis or the ovary. Some individuals with a 46,XX karyotype develop testes or ovotestes (testicular or ovotesticular disorder of sex development; TDSD/OTDSD), due to the presence of the testis-determining gene,SRY. Other rare complex syndromic forms of TDSD/OTDSD are associated with mutations in pro-ovarian genes that repress testis development (e.g.WNT4); however, the genetic cause of the more common non-syndromic forms is unknown. Steroidogenic factor-1 (known as NR5A1) is a key regulator of reproductive development and function. Loss-of-function changes in NR5A1 in 46,XY individuals are associated with a spectrum of phenotypes in humans ranging from a lack of testis formation to male infertility. Mutations inNR5A1in 46,XX women are associated with primary ovarian insufficiency, which includes a lack of ovary formation, primary and secondary amenorrhoea as well as early menopause. Here, we show that a specific recurrent heterozygous missense mutation (p.Arg92Trp) in the accessory DNA-binding region of NR5A1 is associated with variable degree of testis development in 46,XX children and adults from four unrelated families. Remarkably, in one family a sibling raised as a girl and carrying thisNR5A1mutation was found to have a 46,XY karyotype with partial testicular dysgenesis. These unique findings highlight how a specific variant in a developmental transcription factor can switch organ fate from the ovary to testis in mammals and represents the first missense mutation causing isolated, non-syndromic 46,XX testicular/ovotesticular DSD in humans.
影响因子：
3.5
作者：
Bashamboo A;Donohoue PA;Vilain E;Rojo S;Calvel P;Seneviratne SN;Buonocore F;Barseghyan H;Bingham N;Rosenfeld JA;Mulukutla SN;Jain M;Burrage L;Dhar S;Balasubramanyam A;Lee B;Members of UDN;Dumargne MC;Eozenou C;Suntharalingham JP;de Silva K;Lin L;Bignon-Topalovic J;Poulat F;Lagos CF;McElreavey K;Achermann JC
通讯作者：
Achermann JC