Pular para o conteúdo
Merck
  • Genetic screening and functional analysis of CASP9 mutations in a Chinese cohort with neural tube defects.

Genetic screening and functional analysis of CASP9 mutations in a Chinese cohort with neural tube defects.

CNS neuroscience & therapeutics (2018-01-25)
Xiao-Zhen Liu, Qin Zhang, Qian Jiang, Bao-Ling Bai, Xiao-Juan Du, Fang Wang, Li-Hua Wu, Xiao-Lin Lu, Yi-Hua Bao, Hui-Li Li, Ting Zhang
RESUMO

Neural tube defects (NTDs) are birth defects of the nervous system and are the second most frequent cause of birth defects worldwide. The etiology of NTDs is complicated and involves both genetic and environmental factors. CASP9 is an initiator caspase in the intrinsic apoptosis pathway, which in Casp9-/- mice has been shown to result in NTDs because of decreased apoptosis. The aim of this study was to evaluate the potential genetic contribution of the CASP9 gene in human NTDs. High-throughput sequencing was performed to screen genetic variants of CASP9 genes in 355 NTD cases and 225 matched controls. Apoptosis-relevant assays were performed on transiently transfected E9 neuroepithelial cells or human embryonic kidney 293T cells, to determine the functional characteristics of NTD-specific rare variants under complete or low folic acid (FA) status. We found significant expression of CASP9 rare variants in NTDs and identified 4 NTD-specific missense variants. Functional assays demonstrated that a p.Y251C variant attenuates apoptosis by reducing CASP9 protein expression and decreasing activity of the intrinsic apoptosis pathway. From this, we conclude that this variant may represent a loss-of-function mutation. A 4-time recurrent p.R191G variant did not affect intrinsic apoptosis in complete medium, while it completely inhibited apoptosis induced by low FA medium. Our findings identify a genetic link for apoptosis in human NTDs and highlight the effect of gene-environment interactions in a complex disease.

MATERIAIS
Número do produto
Marca
Descrição do produto

Sigma-Aldrich
Anti-Myc Tag Antibody, clone 4A6, biotin conjugate, clone 4A6, Upstate®, from mouse