Variants in TNIP1, a regulator of the NF-kB pathway, found in two patients with neural tube defects

Carpia, Francesca La; Rendeli, Claudia; Molinario, Clelia; Milillo, Annamaria; Farroni, Chiara; Caproş, Natalia; Ausili, Emanuele; Paolucci, V.; Neri, G; Romagnoli, Costantino; Sangiorgi, Eugenio; Gurrieri, Fiorella

doi:10.1007/s00381-016-3087-1

Cited by 6 publications

(1 citation statement)

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“…Overexpression of TRIM4 potentiated virus-triggered activation of IRF3 and NF-kB, as well as IFN-b induction, whereas knockdown of TRIM4 had opposite effects, suggesting that TRIM4 is an important regulator of virus-induced IFN induction pathways during innate antiviral responses [35]. Mutations in TNIP1, a gene whose main role is downregulation of the NF-kB pathway, were found in NTD patients [36], and knockout of genes involved in the NF-kB pathway, including Bcl10, IKKa, IKKb, and TRAF6, showed NTD-related phenotypes in embryonic stages in mice [37–39]. These results suggest that the genes involved in the NF-kB pathway demonstrate a relationship with NTDs and that TRIM4 might participate in the etiology of NTDs via regulation of innate immune responses, including NF-kB signaling.…”

Section: Discussionmentioning

confidence: 99%

TRIM4 is associated with neural tube defects based on genome-wide DNA methylation analysis

Zhang

Guo

et al. 2019

Clin Epigenet

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BackgroundNeural tube defects (NTDs) are complex abnormalities associated with gene-environment interactions. The underlying cause has not been determined.MethodsSpinal cord tissues from cases with NTDs and healthy controls were collected. Methylation patterns between cases and normal individuals were compared using 450K Infinium Methylation BeadChip Illumina. DNA methylation analysis by pyrosequencing (PyroMark Q96) and mRNA and protein expression were analyzed using real-time quantitative PCR and Western blotting, respectively. Next-generation and Sanger sequencing were used to determine genetic variants in the target genes.ResultsSpinal cord tissues from cases with NTDs had more hypomethylated than hypermethylated genes. Further evaluation showed that the exon 1 region of TRIM4 was hypomethylated, and TRIM4 mRNA and protein levels were significantly increased in NTDs compared to controls. A rare missense variant (rs76665876) in TRIM4 was found in 3 of the 14 NTD cases but was not related to TRIM4 expression. TRIM4 mRNA levels were significantly increased in cases with hypomethylation and without the rs76665876 variant.ConclusionThese findings suggest that spinal cord tissues in cases with NTDs had a different genome-wide methylation pattern compared to controls. Abnormal methylation patterns in TRIM4 in immunity pathways might be involved in NTD pathogenesis. Genetic variants in TRIM4 genes only slightly contribute to the etiology of human NTDs.Electronic supplementary materialThe online version of this article (10.1186/s13148-018-0603-z) contains supplementary material, which is available to authorized users.

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