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.

中文翻译：

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TAF8 突变导致神经退行性疾病。

TAF8 是转录因子 II D 复合物的一部分，由 TATA 结合蛋白和 13 个 TATA 结合蛋白相关因子 (TAF) 组成。转录因子 II D 是第一个在启动子处募集以组装 RNA 聚合酶 II 预起始复合物的通用转录因子。迄今为止，已经描述了与人类转录因子 II D 的 13 个亚基中的 5 个中的变异有关的疾病。最近，有报道称一名儿童在 TAF8 中具有纯合子 c.781-1G>A 突变。在这里，我们描述了另外七名 TAF8 突变的患者，从而证实了 TAF8 相关疾病。在两名同胞患者中，我们发现了两个新的复合杂合 TAF8 剪接位点突变，c.45+4A > G 和 c.489G> A，它们导致异常剪接以及 TAF8 的表达减少和错误定位。在另外五名患者中，先前描述的 c.781-1G > 两个等位基因上都存在一个突变。与不同 TAF8 突变相关的临床表型的特征是严重的精神运动迟缓，几乎没有发育、喂养问题、小头畸形、生长迟缓、痉挛和癫痫。脑成像显示髓鞘形成、胼胝体变薄和脑萎缩。此外，兄弟姐妹对的重复成像显示进行性脑和小脑萎缩。一致地，在磁共振波谱上观察到减少的 N-乙酰天冬氨酸，一种神经元活力的标志物。对文献的进一步审查表明，导致转录因子 II D 亚基表达降低的突变具有小头畸形、发育迟缓和智力障碍的重叠表型。尽管转录因子 II D 在所有细胞和组织中的 RNA 聚合酶 II 转录中起重要作用，但与此类缺陷相关的症状几乎完全是神经系统的。这可能表明神经元组织对基因表达的广泛失调具有特定的脆弱性，这也见于 Rett 综合征或 Cornelia de Lange 综合征。