Haploinsufficiency of Dmxl2, encoding a synaptic protein, causes infertility associated with a loss of GnRH neurons in mouse.
Haploinsufficiency of Dmxl2, encoding a synaptic protein, causes infertility associated with a loss of GnRH neurons in mouse.
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DOI：
10.1371/journal.pbio.1001952
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发表时间：
2014-09
期刊：
影响因子：
9.8
通讯作者：
de Roux N
中科院分区：
文献类型：
--
作者：
Tata B;Huijbregts L;Jacquier S;Csaba Z;Genin E;Meyer V;Leka S;Dupont J;Charles P;Chevenne D;Carel JC;Léger J;de Roux N
Rabconnectin-3α和青春期的控制人类遗传学表明，低水平的Rabconnectin-3α会导致产生促性腺激素释放激素的神经元的损失，揭示了青春期不完全和不育的新机制。引起促性腺激素缺乏症的遗传缺陷的表征对阐明Kisspeptins和神经激肽B在青春期开始和生殖中的基本作用做出了重大贡献。青春期的缺失也可能揭示了由各种细胞通路中的分子缺陷引起的神经发育障碍。这些神经发育障碍的调查可能会提供有关控制青春期开始和生殖能力的神经元过程的信息。我们在这里描述一个新的综合征观察三兄弟，其中涉及促性腺激素轴缺陷，中枢性甲状腺功能减退症，外周脱髓鞘感觉运动性多发性神经病，精神发育迟滞，和深刻的低血糖症，进展为非自身免疫性胰岛素依赖型糖尿病。高通量测序显示，在所有三名受影响的患者中，DMXL 2中有15个核苷酸的纯合框内缺失。这种纯合性缺失与患者血液淋巴细胞中较低的DMXL 2 mRNA水平相关。DMXL 2编码突触蛋白rabconnectin-3α，其已被鉴定为Rab 3-GAP和Rab 3-GEP（GTTR Rab 3a的两种调节剂）的推定支架蛋白。我们发现rabconnectin-3α在下丘脑正中隆起的促性腺激素释放激素（GnRH）轴突末端的胞吐囊泡中表达。在垂体内表达促黄体生成素（LH）和促卵泡激素（FSH）的细胞中也特异性表达。从小鼠神经元中有条件地杂合缺失Dmxl 2延迟了青春期并导致非常低的生育力。这种生殖表型与成年小鼠下丘脑中GnRH神经元数量较少有关。最后，在胰岛素分泌细胞系中敲低Dmxl 2表明rabconnectin-3α控制胰岛素的组成性分泌和葡萄糖诱导的分泌。总之，这项研究表明，低水平的DMXL 2表达导致一个复杂的神经系统表型，异常的葡萄糖代谢和促性腺激素轴缺陷由于GnRH神经元的损失。我们的研究结果确定rabconectin-3α作为神经元和内分泌稳态过程的关键控制器。对青春期异常的神经发育障碍的研究可以揭示控制青春期开始和随后的生殖功能的神经元过程。我们在这里描述一个新的综合征观察三兄弟青春期不完全，中枢性甲状腺功能减退，周围多发性神经病，精神发育迟滞，和异常的葡萄糖调节。在这个近亲家庭的分子遗传学研究显示，在DMXL 2基因的15个核苷酸的框内缺失，这导致其表达水平较低。我们发现，由DMXL 2编码的突触蛋白rabconnectin-3α在大脑和产生促性腺激素释放激素（GnRH）的神经元轴突末端广泛表达。然后，我们观察到，神经元特异性缺失的一个等位基因的Dmxl 2在小鼠再现不完全的青春期中看到的人类患者，并在下丘脑中的GnRH神经元的数量减少的结果。我们还发现rabconnectin-3α控制葡萄糖诱导的胰岛素分泌。这些发现揭示了促性腺激素缺乏的新机制，并确定rabconnectin-3α是神经元和内分泌稳态的关键控制器。
Rabconnectin-3α and the control of puberty Human genetics shows that low levels of rabconnectin-3α cause a loss of the neurons that produce gonadotropin-releasing hormone, revealing a new mechanism for incomplete puberty and infertility. Characterization of the genetic defects causing gonadotropic deficiency has made a major contribution to elucidation of the fundamental role of Kisspeptins and Neurokinin B in puberty onset and reproduction. The absence of puberty may also reveal neurodevelopmental disorders caused by molecular defects in various cellular pathways. Investigations of these neurodevelopmental disorders may provide information about the neuronal processes controlling puberty onset and reproductive capacity. We describe here a new syndrome observed in three brothers, which involves gonadotropic axis deficiency, central hypothyroidism, peripheral demyelinating sensorimotor polyneuropathy, mental retardation, and profound hypoglycemia, progressing to nonautoimmune insulin-dependent diabetes mellitus. High-throughput sequencing revealed a homozygous in-frame deletion of 15 nucleotides in DMXL2 in all three affected patients. This homozygous deletion was associated with lower DMXL2 mRNA levels in the blood lymphocytes of the patients. DMXL2 encodes the synaptic protein rabconnectin-3α, which has been identified as a putative scaffold protein for Rab3-GAP and Rab3-GEP, two regulators of the GTPase Rab3a. We found that rabconnectin-3α was expressed in exocytosis vesicles in gonadotropin-releasing hormone (GnRH) axonal extremities in the median eminence of the hypothalamus. It was also specifically expressed in cells expressing luteinizing hormone (LH) and follicle-stimulating hormone (FSH) within the pituitary. The conditional heterozygous deletion of Dmxl2 from mouse neurons delayed puberty and resulted in very low fertility. This reproductive phenotype was associated with a lower number of GnRH neurons in the hypothalamus of adult mice. Finally, Dmxl2 knockdown in an insulin-secreting cell line showed that rabconnectin-3α controlled the constitutive and glucose-induced secretion of insulin. In conclusion, this study shows that low levels of DMXL2 expression cause a complex neurological phenotype, with abnormal glucose metabolism and gonadotropic axis deficiency due to a loss of GnRH neurons. Our findings identify rabconectin-3α as a key controller of neuronal and endocrine homeostatic processes. Investigation of neurodevelopmental disorders with abnormal puberty can reveal neuronal processes that control the initiation of puberty and subsequent reproductive function. We describe here a new syndrome observed in three brothers with incomplete puberty, central hypothyroidism, peripheral polyneuropathy, mental retardation, and abnormal glucose regulation. Molecular genetic investigation in this consanguineous family revealed an in-frame deletion of 15 nucleotides in the DMXL2 gene, which resulted in lower levels of its expression. We found that rabconnectin-3α, the synaptic protein encoded by DMXL2, is widely expressed in the brain and in the ends of the axons of neurons that produce gonadotropin-releasing hormone (GnRH). We then observed that neuron-specific deletion of one allele of Dmxl2 in mice reproduces the incomplete puberty seen in the human patients and results in decreased numbers of GnRH neurons in the hypothalamus. We also showed that rabconnectin-3α controls glucose-induced insulin secretion. These findings reveal a new mechanism of gonadotropin deficiency and identify rabconnectin-3α as a key controller of neuronal and endocrine homeostasis.
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RAB GTPases在膜交通和细胞生理学中的作用。
影响因子：
33.6
作者：
Hutagalung AH;Novick PJ
通讯作者：
Novick PJ
多个成纤维细胞生长因子信号传导成分中的复合缺陷会差异影响鼠促性腺营养蛋白释放激素系统。
影响因子：
3.2
作者：
Chung WC;Matthews TA;Tata BK;Tsai PS
通讯作者：
Tsai PS
DOI：
10.1074/jbc.m804134200
发表时间：
2008-08-22
期刊：
The Journal of biological chemistry
影响因子：
--
作者：
Figueiredo AC;Wasmeier C;Tarafder AK;Ramalho JS;Baron RA;Seabra MC
通讯作者：
Seabra MC
影响因子：
3.1
作者：
Dode, C.;Hardelin, J. -P.
通讯作者：
Hardelin, J. -P.
DOI：
10.1073/pnas.1834399100
发表时间：
2003-09-16
影响因子：
11.1
作者：
de Roux, N;Genin, E;Milgrom, E
通讯作者：
Milgrom, E