FKBP8 variants are risk factors for spina bifida.
FKBP8 variants are risk factors for spina bifida.
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DOI：
10.1093/hmg/ddaa211
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发表时间：
2020-09
影响因子：
3.5
通讯作者：
T. Tian;Xuanye Cao;Sung-Eun Kim;Y. Lin;J. Steele;Robert M. Cabrera;Menuka Karki;Wei Yang;N. J. Marini;Ethan N Hoffman;Xiao Han;Cindy X. Hu;Linlin Wang;B. Wlodarczyk;G. Shaw;A. Ren;R. Finnell;Y. Lei
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文献类型：
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作者：
T. Tian;Xuanye Cao;Sung-Eun Kim;Y. Lin;J. Steele;Robert M. Cabrera;Menuka Karki;Wei Yang;N. J. Marini;Ethan N Hoffman;Xiao Han;Cindy X. Hu;Linlin Wang;B. Wlodarczyk;G. Shaw;A. Ren;R. Finnell;Y. Lei
神经管畸形是由胚胎发育早期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NTDS的遗传病因学仍然知之甚少。FKBP8是哺乳动物神经管关闭的关键。Fkbp8-/-小鼠胚胎显示后部NTDS与脊柱裂(SB)的诊断一致。到目前为止，还没有任何出版物报道FKBP8与人类NTDS之间存在任何关联。对472例SB和565例对照的基因组DNA进行Sanger测序，在SB患者中发现了5个罕见的有害变异(MAF=0.001)，而在对照中没有发现罕见的有害变异(P=0.0191)。P.Glu140*影响FKBP8定位于线粒体，并产生截短形式的FKBP8蛋白，从而损害其与bcl2的相互作用，最终导致细胞凋亡增加。P.Ser3Leu、p.Lys315Asn和p.Ala292Ser变异体降低FKBP8蛋白水平。P.Lys315Asn进一步增加细胞的凋亡率。从E9.5和E10.5的Fkbp8-/-小鼠和野生型小鼠分离的前后部组织的RNA测序表明，Fkbp8-/-胚胎在后部获得的组织中存在异常表达谱，从而导致后部NTD。此外，我们还发现Fkbp8基因敲除的小鼠胚胎在神经管发育的早期存在Wnt3a和Nkx2.9的异常表达，可能也参与了尾部特异性NTDS的发生。这些发现为FKBP8的功能变异是SB的危险因素提供了证据，这可能涉及一种新的机制，Fkbp8突变通过这种新机制特异性地引起小鼠SB。
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.