Pathogenic variants in RNPC3 are associated with hypopituitarism and primary ovarian insufficiency.
Pathogenic variants in RNPC3 are associated with hypopituitarism and primary ovarian insufficiency.
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DOI：
10.1016/j.gim.2021.09.019
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发表时间：
2022-03
期刊：
影响因子：
--
通讯作者：
Dattani MT
中科院分区：
文献类型：
--
作者：
Akin L;Rizzoti K;Gregory LC;Corredor B;Le Quesne Stabej P;Williams H;Buonocore F;Mouilleron S;Capra V;McGlacken-Byrne SM;Martos-Moreno GÁ;Azmanov DN;Kendirci M;Kurtoglu S;Suntharalingham JP;Galichet C;Gustincich S;Tasic V;Achermann JC;Accogli A;Filipovska A;Tuilpakov A;Maghnie M;Gucev Z;Gonen ZB;Pérez-Jurado LA;Robinson I;Lovell-Badge R;Argente J;Dattani MT
我们的目的是调查潜在的一种新的表型，包括垂体功能减退与POI的分子基础。我们使用NGS来识别所有家系中的变异。Rnpc 3/RNPC 3的表达通过鼠/人胚胎切片上的原位杂交进行分析。Crispr/Cas9用于产生在保守的鼠Rnpc 3 RRM 2结构域中携带p.L483F致病性变体的小鼠。我们描述了15例来自9个家系的RNPC 3双等位基因突变的患者，RNPC 3编码一种小剪接体的特异性蛋白质组分，与包括严重GHD、低泌乳素血症、可变TSH缺乏症和垂体前叶发育不全在内的低血糖表型相关。POI被诊断为八个受影响的女性，而男性性腺功能正常。此外，2只受影响的雄性动物在GH治疗后显示正常生长，尽管存在重度生化GHD。在小鼠和人类胚胎中，Rnpc 3/RNPC 3在发育中的前脑中表达，包括下丘脑和Rathke囊。雌性rnpc 3突变小鼠显示垂体GH含量减少，但在年轻小鼠中没有生殖障碍。雄性小鼠无明显表型。我们的研究结果提出了新的见解RNPC 3在女性特定的性腺功能中的作用，并强调了小剪接体在垂体和卵巢发育和功能中的关键作用。
We aimed to investigate the molecular basis underlying a novel phenotype including hypopituitarism associated with POI. We used NGS to identify variants in all pedigrees. Expression of Rnpc3/RNPC3 was analysed by in situ hybridization on murine/human embryonic sections. Crispr/Cas9 was used to generate mice carrying the p.L483F pathogenic variant in the conserved murine Rnpc3 RRM2 domain. We described 15 patients from nine pedigrees with biallelic mutations in RNPC3, encoding a specific protein component of the minor spliceosome, associated with a hypopituitary phenotype including severe GHD, hypoprolactinaemia, variable TSH deficiency and anterior pituitary hypoplasia. POI was diagnosed in eight of nine affected females whilst males had normal gonadal function. Additionally, two affected males displayed normal growth off GH treatment, despite severe biochemical GHD. In both mouse and human embryos, Rnpc3/RNPC3 was expressed in the developing forebrain including the hypothalamus and Rathke’s pouch. Female rnpc3 mutant mice displayed a reduction in pituitary GH content, but with no reproductive impairment in young mice. Male mice exhibited no obvious phenotype. Our findings suggest novel insights into the role of RNPC3 in female-specific gonadal function and emphasize a critical role of the minor spliceosome in pituitary and ovarian development and function.
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DOI：
10.1056/nejmoa1309635
发表时间：
2014-03-06
期刊：
The New England journal of medicine
影响因子：
--
作者：
Caburet S;Arboleda VA;Llano E;Overbeek PA;Barbero JL;Oka K;Harrison W;Vaiman D;Ben-Neriah Z;García-Tuñón I;Fellous M;Pendás AM;Veitia RA;Vilain E
通讯作者：
Vilain E
影响因子：
11.1
作者：
Argente, Jesus;Flores, Raquel;Gutierrez-Arumi, Armand;Verma, Bhupendra;Martos-Moreno, Gabriel A.;Cusco, Ivon;Oghabian, Ali;Chowen, Julie A.;Frilander, Mikko J.;Perez-Jurado, Luis A. '
通讯作者：
Perez-Jurado, Luis A. '
影响因子：
3.9
作者：
Beysen, Diane;De Paepe, Anne;De Baere, Elfride
通讯作者：
De Baere, Elfride
影响因子：
9.8
作者：
Antonellis, A;Ellsworth, RE;Green, ED
通讯作者：
Green, ED
原发性卵巢功能不全的遗传学：新进展和机遇
影响因子：
13.3
作者：
Qin Y;Jiao X;Simpson JL;Chen ZJ
通讯作者：
Chen ZJ