SEMA3A, a gene involved in axonal pathfinding, is mutated in patients with Kallmann syndrome.
SEMA3A, a gene involved in axonal pathfinding, is mutated in patients with Kallmann syndrome.
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DOI：
10.1371/journal.pgen.1002896
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发表时间：
2012-08
期刊：
影响因子：
4.5
通讯作者：
Dodé C
中科院分区：
文献类型：
--
作者：
Hanchate NK;Giacobini P;Lhuillier P;Parkash J;Espy C;Fouveaut C;Leroy C;Baron S;Campagne C;Vanacker C;Collier F;Cruaud C;Meyer V;García-Piñero A;Dewailly D;Cortet-Rudelli C;Gersak K;Metz C;Chabrier G;Pugeat M;Young J;Hardelin JP;Prevot V;Dodé C
Kallmann综合征（KS）与先天性性腺功能减退症有关，这是由于促性腺激素释放激素（GnRH）缺乏和嗅觉丧失所致。KS的遗传学涉及多种传播方式，包括寡基因遗传。在这里，我们报告说，Nrp 1 sema/sema突变小鼠缺乏一个功能性的脑信号蛋白结合结构域的神经纤毛蛋白-1，一个强制性的辅助受体的脑信号蛋白-3A，有KS样表型。对这些小鼠的病理组织学分析确实显示外周嗅觉系统发育异常，神经内分泌GnRH细胞向基底前脑的胚胎迁移缺陷，这导致新生小鼠死亡率增加，成年小鼠生育力降低。因此，我们筛选了386名KS患者SEMA 3A突变的存在（通过对所有17个编码外显子和侧翼剪接位点进行桑格测序），并在24名患者中鉴定了非同义突变，具体地说，一个移码小缺失（D538 fsX 31）和七个不同的错义突变（R66 W，N153 S，I400 V，V435 I，T688 A，R730 Q，R733 H）。所有突变均为杂合状态。7个突变导致转染的COS-7细胞（D538 fsX 31、R66 W、V435 I）的脑信号蛋白-3A分泌受损，或来自胚胎GnRH细胞的GN 11细胞系（N153 S、I400 V、T688 A、R733 H）中分泌蛋白的信号传导活性降低，这强烈表明这些突变具有致病作用。值得注意的是，在这些患者中的5例中，已经在杂合状态下鉴定出其他KS基因的突变。我们的研究结果表明，semaphorin-3A信号传导不足有助于KS的发病机制，并进一步证实了这种发育障碍的遗传寡基因模式。卡尔曼综合征是一种遗传性发育疾病，影响荷尔蒙生殖轴和嗅觉。生殖障碍和嗅觉障碍之间存在发育联系：产生促性腺激素释放激素的神经内分泌细胞在胚胎期通常会沿着沿着嗅觉神经纤维从鼻子迁移到前脑，但在患者身上却没有这样做。受影响的个体通常不会经历自发的青春期。激素替代疗法是一种开始男性男性化或女性乳房发育，然后在两性中发展生育能力的治疗方法。这是一种遗传异质性疾病。迄今为止，在大约30%的受影响个体中发现了8个致病基因中的任何一个突变，这表明其他基因仍有待发现。我们报告的鉴定，在6%的KS患者，各种功能丧失突变的基因编码的semaphorin-3A，一种分泌蛋白参与导航的嗅神经纤维在胚胎发育过程中。这些突变中的许多也在临床上未受影响的个体中检测到的事实表明，它们必须与其他遗传缺陷联合收割机结合以产生疾病表型。
Kallmann syndrome (KS) associates congenital hypogonadism due to gonadotropin-releasing hormone (GnRH) deficiency and anosmia. The genetics of KS involves various modes of transmission, including oligogenic inheritance. Here, we report that Nrp1 sema/sema mutant mice that lack a functional semaphorin-binding domain in neuropilin-1, an obligatory coreceptor of semaphorin-3A, have a KS–like phenotype. Pathohistological analysis of these mice indeed showed abnormal development of the peripheral olfactory system and defective embryonic migration of the neuroendocrine GnRH cells to the basal forebrain, which results in increased mortality of newborn mice and reduced fertility in adults. We thus screened 386 KS patients for the presence of mutations in SEMA3A (by Sanger sequencing of all 17 coding exons and flanking splice sites) and identified nonsynonymous mutations in 24 patients, specifically, a frameshifting small deletion (D538fsX31) and seven different missense mutations (R66W, N153S, I400V, V435I, T688A, R730Q, R733H). All the mutations were found in heterozygous state. Seven mutations resulted in impaired secretion of semaphorin-3A by transfected COS-7 cells (D538fsX31, R66W, V435I) or reduced signaling activity of the secreted protein in the GN11 cell line derived from embryonic GnRH cells (N153S, I400V, T688A, R733H), which strongly suggests that these mutations have a pathogenic effect. Notably, mutations in other KS genes had already been identified, in heterozygous state, in five of these patients. Our findings indicate that semaphorin-3A signaling insufficiency contributes to the pathogenesis of KS and further substantiate the oligogenic pattern of inheritance in this developmental disorder. Kallmann syndrome is a hereditary developmental disease that affects both the hormonal reproductive axis and the sense of smell. There is a developmental link between the reproductive and olfactory disorders: neuroendocrine cells producing the gonadotropin-releasing hormone that is deficient in the patients normally migrate from the nose to the forebrain along olfactory nerve fibers during embryonic life, and they fail to do so in the patients. Affected individuals usually do not undergo spontaneous puberty. Hormone replacement therapy is the treatment to initiate virilization in males or breast development in females and later to develop fertility in both sexes. This is a genetically heterogeneous disease. Mutations in any of eight causative genes identified so far have been found in approximately 30% of the affected individuals, thus indicating that other genes remain to be discovered. We report on the identification, in 6% of the KS patients, of various loss-of-function mutations in the gene coding for semaphorin-3A, a secreted protein involved in the navigation of olfactory nerve fibers during embryogenesis. The fact that many of these mutations were also detected in clinically unaffected individuals indicates that they must combine with other genetic defects to produce the disease phenotype.
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影响因子：
7.8
作者：
Giacobini, Paolo;Messina, Andrea;Morello, Francesca;Ferraris, Nicoletta;Corso, Simona;Penachioni, Junia;Giordano, Silvia;Tamagnone, Luca;Fasolo, Aldo
通讯作者：
Fasolo, Aldo
影响因子：
30.8
作者：
Dodé, C;Levilliers, J;Hardelin, JP
通讯作者：
Hardelin, JP
影响因子：
3.5
作者：
Cariboni, Anna;Davidson, Kathryn;Ruhrberg, Christiana
通讯作者：
Ruhrberg, Christiana
DOI：
10.1242/dev.063362
发表时间：
2011-09
期刊：
Development (Cambridge, England)
影响因子：
--
作者：
Cariboni A;Davidson K;Dozio E;Memi F;Schwarz Q;Stossi F;Parnavelas JG;Ruhrberg C
通讯作者：
Ruhrberg C
影响因子：
15.9
作者：
Teixeira, Luis;Guimiot, Fabien;Hardelin, Jean-Pierre
通讯作者：
Hardelin, Jean-Pierre