TAF1, associated with intellectual disability in humans, is essential for embryogenesis and regulates neurodevelopmental processes in zebrafish

Abstract

The TATA-box binding protein associated factor 1 (TAF1) protein is a key unit of the transcription factor II D complex that serves a vital function during transcription initiation. Variants of TAF1 have been associated with neurodevelopmental disorders, but TAF1 ’s molecular functions remain elusive. In this study, we present a five-generation family affected with X-linked intellectual disability that co-segregated with a TAF1 c.3568C>T, p.(Arg1190Cys) variant. All affected males presented with intellectual disability and dysmorphic features, while heterozygous females were asymptomatic and had completely skewed X-chromosome inactivation. We investigated the role of TAF1 and its association to neurodevelopment by creating the first complete knockout model of the TAF1 orthologue in zebrafish. A crucial function of human TAF1 during embryogenesis can be inferred from the model, demonstrating that intact taf1 is essential for embryonic development. Transcriptome analysis of taf1 zebrafish knockout revealed enrichment for genes associated with neurodevelopmental processes. In conclusion, we propose that functional TAF1 is essential for embryonic development and specifically neurodevelopmental processes.

Missense variants in TAF1 and developmental phenotypes: Challenges of determining pathogenicity

“…To date, only missense variants have been found; the lack of hemi‐ and homozygous loss‐of‐function variants in the protein coding part of the canonical TAF1 isoform in human population databases suggests that the complete loss of TAF1 may be embryonic‐lethal. This is supported by a recent study in which complete loss of TAF1 causes embryonic lethality in zebrafish (Gudmundsson et al, ). Some recent data have suggested that TAF1 might be involved in altering the morphology and function of the cerebellum and cerebral cortex (Janakiraman et al, ).…”

“…The facial features in Individual 13 and these two boys are similar, with large protruding ears and upturned nasal tip. In addition, this same variant was reported in six individuals with ID and dysmorphic facial features in one large family, as part of a much larger ES study (Hu et al, ), and more clinical details were recently published (Gudmundsson et al, ). This one variant has, therefore, now been identified in three separate families.…”

“…The facial features in Individual 13 and these two boys are similar, with large protruding ears and upturned nasal tip. In addition, this same variant was reported in six individuals with ID and dysmorphic facial features in one large family, as part of a much larger ES study (Hu et al, 2016), and more clinical details were recently published (Gudmundsson et al, 2019 (Yuan et al, 2015). This shared clinical gestalt between mutations in TAF1 and homozygous mutations in TAF6 in an autosomal-recessive disorder with CdLS-like features has led some to refer to CdLS as a transcriptomopathy (Yuan et al, 2015).…”

TAF1 Transcripts and Neurofilament Light Chain as Biomarkers for X‐linked Dystonia‐Parkinsonism

“…[51][52][53][54] Although skewed Xchromosome inactivation has been reported as the underlying mechanism in at least 1 case of an XDPcarrier symptomatic female, 52 it has also been shown to be the underlying protective mechanism against Xlinked neurological diseases caused by TAF1 coding mutations. [55][56][57] We hypothesize that skewed Xchromosome inactivation may attenuate TAF1 dysregulation, which in turn protects female carriers from the downstream effects of a significant decrease in normal TAF1 expression.…”

The genetics of intellectual disability: advancing technology and gene editing

“…Functional study of this gene was performed by using a zebrafish knockout model. Severe phenotypes were observed during embryogenesis and neurodevelopment in the zebrafish TAF1 knockout model 63 . The heterogeneity of ID makes it very difficult to validate candidate genes as causative ID genes, but in vitro and in vivo studies provide grounds for conclusively identifying certain genes.…”