Mutations inTAF8cause a neurodegenerative disorder

Abstract

TAF8 is part of the transcription factor II D complex, composed of the TATA-binding protein and 13 TATA-binding protein–associated factors (TAFs). Transcription factor II D is the first general transcription factor recruited at promoters to assemble the RNA polymerase II preinitiation complex. So far disorders related to variants in 5 of the 13 subunits of human transcription factor II D have been described. Recently, a child with a homozygous c.781-1G>A mutation in TAF8 has been reported. Here we describe seven further patients with mutations in TAF8 and thereby confirm the TAF8 related disorder. In two sibling patients, we identified two novel compound heterozygous TAF8 splice site mutations, c.45+4A > G and c.489G>A, which cause aberrant splicing as well as reduced expression and mislocalization of TAF8. In five further patients, the previously described c.781-1G > A mutation was present on both alleles. The clinical phenotype associated with the different TAF8 mutations is characterized by severe psychomotor retardation with almost absent development, feeding problems, microcephaly, growth retardation, spasticity and epilepsy. Cerebral imaging showed hypomyelination, a thin corpus callosum and brain atrophy. Moreover, repeated imaging in the sibling pair demonstrated progressive cerebral and cerebellar atrophy. Consistently, reduced N-acetylaspartate, a marker of neuronal viability, was observed on magnetic resonance spectroscopy. Further review of the literature shows that mutations causing a reduced expression of transcription factor II D subunits have an overlapping phenotype of microcephaly, developmental delay and intellectual disability. Although transcription factor II D plays an important role in RNA polymerase II transcription in all cells and tissues, the symptoms associated with such defects are almost exclusively neurological. This might indicate a specific vulnerability of neuronal tissue to widespread deregulation of gene expression as also seen in Rett syndrome or Cornelia de Lange syndrome.

RNA polymerase II transcription with partially assembled TFIID complexes

“…In conclusion, our study supports the vision of a much more dynamic and flexible Pol II transcription initiation machinery. Interestingly, this flexibility has some impact on human physiopathology as a growing number of mutations have been identified in TAF1 , TAF2 , TAF4 , TAF6 , TAF8 and TAF13 genes, in patients associated with neurodevelopmental defects and intellectual disabilities 58,77,78 . Surprisingly, these mutations mainly affect the brain development and function but without any major effect on the other organs, clearly suggesting that the transcription initiation machinery has a certain degree of adaptability but that the cellular context is a main constraint.…”

Participation of the TBP‐associated factors (TAFs) in cell differentiation

“…Finally, TAF8 has been linked to neurodegenerative disorders characterized by hypomyelination, a thin corpus callosum, and brain atrophy (Wong et al, 2022). Such alterations are associated with heterozygosity for several gene variants, including the intronic TAF8 variant GRCh38:chr6:g.42050590A>G and the exonic TAF8 variant GRCh38:chr6:g.42057513G > A (Wong et al, 2022).…”

“…Finally, TAF8 has been linked to neurodegenerative disorders characterized by hypomyelination, a thin corpus callosum, and brain atrophy (Wong et al, 2022). Such alterations are associated with heterozygosity for several gene variants, including the intronic TAF8 variant GRCh38:chr6:g.42050590A>G and the exonic TAF8 variant GRCh38:chr6:g.42057513G > A (Wong et al, 2022). It has been reported that TAF8 is an integral subunit of the functionally active TFIID, essential for integrating TAF10, an action mediated by its histone‐fold domain (Guermah et al, 2003).…”