Neural tube defects (NTDs) are a group of severe congenital malformations caused by a failure of neural tube closure during early embryonic development. Although extensively investigated, the genetic etiology of NTDs remains poorly understood. FKBP8 is critical for proper mammalian neural tube closure. Fkbp8^−/− mouse embryos showed posterior NTDs consistent with a diagnosis of spina bifida (SB). To date, no publication has reported any association between FKBP8 and human NTDs. Using Sanger sequencing on genomic DNA samples from 472 SB and 565 control samples, we identified 5 rare (MAF < =0.001) deleterious variants in SB patients, while no rare deleterious variant was identified in the controls (p = 0.0191). p.Glu140* affected FKBP8 localization to the mitochondria and created a truncated form of the FKBP8 protein, thus impairing its interaction with BCL2 and ultimately leading to an increase in cellular apoptosis. p.Ser3Leu, p.Lys315Asn and p.Ala292Ser variants decreased FKBP8 protein levels. p.Lys315Asn further increased the cellular apoptosis. RNA sequencing on anterior and posterior tissues isolated from Fkbp8^−/− and wildtype mice at E9.5 and E10.5 showed that Fkbp8^−/− embryos have an abnormal expression profile within tissues harvested at posterior sites, thus leading to a posterior NTD. Moreover, we found that Fkbp8 knockout mouse embryos have abnormal expression of Wnt3a and Nkx2.9 during the early stage of neural tube development, perhaps also contributing to caudal specific NTDs. These findings provide evidence that functional variants of FKBP8 are risk factors for SB, which may involve a novel mechanism by which Fkbp8 mutations specifically cause SB in mice.

中文翻译：

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FKBP8 变体是脊柱裂的危险因素。

神经管缺陷（NTDs）是胚胎早期发育过程中神经管闭合失败引起的一组严重的先天性畸形。尽管进行了广泛的研究，但 NTD 的遗传病因仍然知之甚少。FKBP8对哺乳动物神经管的正确闭合至关重要。Fkbp8 ^-/-小鼠胚胎显示出与脊柱裂 (SB) 诊断一致的后部 NTD。迄今为止，没有出版物报道FKBP8之间有任何关联和人类 NTD。对来自 472 个 SB 和 565 个对照样本的基因组 DNA 样本使用 Sanger 测序，我们在 SB 患者中发现了 5 个罕见的 (MAF < = 0.001) 有害变异，而在对照中没有发现罕见的有害变异 (p = 0.0191)。p.Glu140* 影响 FKBP8 定位到线粒体并产生截短形式的 FKBP8 蛋白，从而削弱其与 BCL2 的相互作用并最终导致细胞凋亡增加。p.Ser3Leu、p.Lys315Asn 和 p.Ala292Ser 变体降低了 FKBP8 蛋白水平。p.Lys315Asn 进一步增加了细胞凋亡。在 E9.5 和 E10.5 从Fkbp8 ^-/-和野生型小鼠分离的前部和后部组织的 RNA 测序显示Fkbp8 ^-/-胚胎在后部采集的组织内具有异常的表达谱，从而导致后部 NTD。此外，我们发现Fkbp8敲除小鼠胚胎在神经管发育的早期阶段具有Wnt3a和Nkx2.9的异常表达，这可能也有助于尾部特异性 NTD。这些发现提供了证据表明FKBP8的功能变异是SB 的危险因素，这可能涉及Fkbp8突变特异性导致小鼠 SB 的新机制。