CTBP1 and CTBP2 mutations underpinning neurological disorders: a systematic review

Abstract

C-terminal binding proteins (CtBP1/2) are transcriptional coregulators that play a significant role during vertebrate neurodevelopment. This systematic review aims to identify case reports with genetic variants in CTBP1 and CTBP2 associated with brain development syndromes.We screened different databases (PubMed, Scopus, Google Scholar, LILACS) by systematically searching journals and checking reference lists and citations of background papers. We found fourteen cases (10 males) from five papers carrying two pathogenic, heterozygous variants in the CTBP1 gene (13 individuals carried the missense mutation c.991C T, p.Arg342Trp, and one subject carrying the 2-base pair deletion c.1315_1316delCA, p.Gln439ValfsTer84). These mutations were de novo in 13 cases and one case of maternal germinal mosaicism. Two variants are in the same domain of the protein: Pro-Leu-Asp-Leu-Ser (PLDLS) C terminal. Patients with these mutations exhibit a phenotype with intellectual disability, HADDTS syndrome (hypotonia, ataxia, developmental delay, and tooth enamel defects), and cerebellar volume loss. We did not identify reported cases associated with homozygous mutations harbored in CTBP1. We did not identify any report of neurodevelopment phenotypes associated with heterozygous or homozygous CTBP2 mutations. Due to CTBP2/RIBEYE being a gene with dual function, identifying and interpreting the potential pathogenic variants is challenging.Further, homozygous mutations in the CTBP2 gene may be lethal. The mechanisms involved in the pathogenesis of neurodevelopment due to variants of these proteins have not yet been elucidated, despite some functional evidence. Further studies should be conducted to understand these transcription factors and their interaction with each other and their partners.

A novel CTBP1 variant in a Chinese pediatric patient with a phenotype distinct from hypotonia, ataxia, developmental delay, and tooth enamel defect syndrome

“…The CTBP1 gene is the only known cause of HADDTS ( Bhatia et al, 2020 ). The gene is widely expressed in brains, liver s, lung s, and it may play a key role in controlling the equilibrium between tubular and stacked structures in the Golgi complex, and functioning in brown adipose tissue (BAT) differentiation ( Acosta-Baena et al, 2022 ). The true prevalence of HADDTS is not well-known because only two pathogenic variants (14 patients) in CTBP1 have been found around the world ( Jafari Khamirani et al, 2021 ).…”

Identification of tRNA-derived small RNAs expression profiles and their potential functions in age-related cataract

“…Among them, CTBP2 was reported to contribute to the formation of posterior capsule opaci cation via affecting the Jagged/Notch signaling pathway [36]. The primary function of the CTBP family members is to be a transcriptional corepressors to act as DNA-binding proteins, chromodomain-containing proteins, and CoREST proteins [37]. Importantly, as mentioned above, oxidative stress of HLECs was the main mechanism for ARC onset, while CTBP2 was also reported to promote the expression of antioxidant genes in response to oxidative insults through forming transcriptional complexes with NRF1 and NRF2 [38].…”

Research Progress of Long Non-Coding RNA in Tumor Drug Resistance: A New Paradigm

“…In prostate cancer patients, C-Terminal binding protein 1 antisense (CTBP1) expression is inhibited by histone deacetylase protein (HAD), induced by the PTB-associated splicing factor (PSF). 10 (2) Transcriptional-level regulation. LncRNA can impact DNA transcription and translation through cis-regulation and transaction, as well as activate transcription factor activity.…”