Year: 2020
Type: article
Study design: Observational Study
Abstract: 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 five 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 level. 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.
Source: Human Molecular Genetics
DOI: 10.1093/hmg/ddaa211
Language: English
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Estimated APC paid: $4,390
Funders: California Department of Public Health, University of Texas at Austin, National Institutes of Health, Centers for Disease Control and Prevention, Department of Mechanical Engineering, University of Texas at Austin, National Institute of Environmental Health Sciences, Eunice Kennedy Shriver National Institute of Child Health and Human Development
Awards: Biomechanics of Neural Tube Development using Brillouin-OCT Multimodality, Risk Genes and Environmental Interactions in Neural Tube Defects, The Role of GPR161 in the Etiology of Neural Tube Defects, CALIFORNIA CENTER OF BD-STEPS II FINDING CAUSES AND PREVENTIVES OF BIRTH DEFECTS, Role of Slc25a32 and Its Interaction with Lrp6 in the Etiology of Neural Tube Defects, Intervention Strategies for Non-Folate Responsive Neural Tube Defects, Folic Acid, Parental Mutation Rates and the Risk for Neural Tube Defects, G9000004251, Training in Precision Environmental Health Sciences
OpenAlex ID: W3088786546