Sema3a plays a role in the pathogenesis of CHARGE syndrome
Sema3a plays a role in the pathogenesis of CHARGE syndrome
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DOI：
10.1093/hmg/ddy045
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发表时间：
2018-04-15
影响因子：
3.5
通讯作者：
Pauli, Silke
中科院分区：
文献类型：
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作者：
Ufartes, Roser;Schwenty-Lara, Janina;Pauli, Silke
电荷综合征是一种常染色体显性遗传性畸形疾病，由染色质重构体CHD7杂合性功能突变引起。CHD7调节Sema3a的表达，这也是Kallmann综合征的发病机制之一，Kallmann综合征是一种典型的以低促性腺激素减退和嗅觉受损为特征的异质性疾病。这两个特征在Charge综合征中都很常见，这表明SEMA3A可能在这些综合征之间提供了基因联系。事实上，我们发现了SEMA3A在Charge综合征的发病机制中发挥作用的证据。首先，CHD7在神经脊细胞中的Sema3a启动子处富含，CHD7功能的丧失抑制了Sema3a的表达。其次，利用非洲爪哇的电荷模型，我们证明了人类SEMA3A可以挽救CHD7功能的丧失。第三，为了阐明除了CHD7突变之外，SEMA3A突变是否也有助于电荷表型的严重程度，我们筛查了31名CHD7阳性患者，并确定了一名SEMA3A杂合子非同义突变患者，c.2002a>；G(p.I668V)。通过分析蛋白质的表达和加工，我们没有观察到P.I668V变体与野生型SEMA3A有任何差异，而最近在Kallmann综合征患者中描述的致病性SEMA3A变体p.R66W确实影响了蛋白质的分泌。此外，P.I668V变种，而不是致病的P.R66W变种，挽救了非洲爪哇CHD7功能的丧失，表明P.I668V变种可能是良性的。因此，SEMA3A是在Charge综合征发病机制中起作用的表观遗传环路的一部分，然而，它似乎不是一个共同的直接修饰物。
CHARGE syndrome is an autosomal dominant malformation disorder caused by heterozygous loss of function mutations in the chromatin remodeler CHD7. Chd7 regulates the expression of Sema3a, which also contributes to the pathogenesis of Kallmann syndrome, a heterogeneous condition with the typical features hypogonadotropic hypogonadism and an impaired sense of smell. Both features are common in CHARGE syndrome suggesting that SEMA3A may provide a genetic link between these syndromes. Indeed, we find evidence that SEMA3A plays a role in the pathogenesis of CHARGE syndrome. First, Chd7 is enriched at the Sema3a promotor in neural crest cells and loss of function of Chd7 inhibits Sema3a expression. Second, using a Xenopus CHARGE model, we show that human SEMA3A rescues Chd7 loss of function. Third, to elucidate if SEMA3A mutations in addition to CHD7 mutations also contribute to the severity of the CHARGE phenotype, we screened 31 CHD7-positive patients and identified one patient with a heterozygous non-synonymous SEMA3A variant, c. 2002A> G (p. I668V). By analyzing protein expression and processing, we did not observe any differences of the p. I668V variant compared with wild-type SEMA3A, while a pathogenic SEMA3A variant p. R66W recently described in a patient with Kallmann syndrome did affect protein secretion. Furthermore, the p. I668V variant, but not the pathogenic p. R66W variant, rescues Chd7 loss of function in Xenopus, indicating that the p. I668V variant is likely benign. Thus, SEMA3A is part of an epigenetic loop that plays a role in the pathogenesis of CHARGE syndrome, however, it seems not to act as a common direct modifier.