Nadav Golan, Odeh Marwan, Mesika Aviv, Abarbanel Har-Tal Yael, Goldfeld Moshe, Zalatkin Tania, Livoff Alejandro, Khoury Raghad Jeris, Sgayer Inshirah, Ben-Sira Liat, Kalfon Limor, Falik-Zaccai Tzipora C
Institute of Human Genetics, Galilee Medical Center, Nahariya, Israel.
The Unit for Ob/Gyn Ultrasound, Galilee Medical Center, Nahariya, Israel.
Eur J Hum Genet. 2025 Jan;33(1):24-29. doi: 10.1038/s41431-024-01679-8. Epub 2024 Aug 21.
TAF8 is part of the transcription factor TFIID complex. TFIID is crucial for recruiting the transcription factor complex containing RNA polymerase II. TAF8 deficiency was recently reported as causing a severe neurodevelopmental disorder in eight patients. We have ascertained three Muslim Arab couples with fetal brain malformations. Clinical, imaging, pathological, biochemical, and molecular analyses were performed. Pre-natal ultrasound performed in four pregnancies revealed massive cerebellar atrophy, microcephaly, cerebral and corpus callosum (CC) anomalies. Pre-natal MRI studies of two of the affected fetuses confirmed microcephaly, small vermis, abnormal sulcation pattern with malformation, and shortening of CC. The fetuses were found to carry a novel likely pathogenic homozygous variant (c.45 + 5 G > A) of TAF8, predicted to affect splicing and presenting autosomal recessive inheritance. Post-mortem examinations confirmed the imaging studies in one fetus. Dysmorphic features including hypertelorism, wide nasal bridge, clinodactyly, and hirsutism were present. Western blotting analysis in fibroblasts of an affected fetus demonstrated a significant reduction of TAF8 protein. We determined high expression levels of TAF8 which progressively diminish in fetal brains of WT mice. We report for the first time the fetal presentation of TAF8 deficiency due to a novel genetic variant, and study TAF8 presence during fetal and neonatal periods in mouse brains. Our study may contribute to understanding the role of TAF8 in the developing human brain.
TAF8是转录因子TFIID复合物的一部分。TFIID对于招募包含RNA聚合酶II的转录因子复合物至关重要。最近有报道称，TAF8缺乏会导致8名患者出现严重的神经发育障碍。我们确定了三对患有胎儿脑畸形的穆斯林阿拉伯夫妇。进行了临床、影像学、病理、生化和分子分析。对4例妊娠进行的产前超声检查显示有大量小脑萎缩、小头畸形、大脑和胼胝体（CC）异常。对2例受影响胎儿进行的产前MRI研究证实了小头畸形、小脑蚓部小、伴有畸形的异常脑沟模式以及CC缩短。发现这些胎儿携带一种新的可能致病的TAF8纯合变异（c.45 + 5 G > A），预计会影响剪接并呈现常染色体隐性遗传。尸检证实了其中1例胎儿的影像学研究结果。存在包括眼距过宽、鼻梁宽、手指弯曲和多毛症等畸形特征。对1例受影响胎儿的成纤维细胞进行的蛋白质印迹分析表明TAF8蛋白显著减少。我们测定了TAF8在野生型小鼠胎儿脑中高表达，且表达水平逐渐降低。我们首次报告了由于一种新的基因变异导致的TAF8缺乏的胎儿表现，并研究了TAF8在小鼠脑胎儿期和新生儿期的存在情况。我们的研究可能有助于理解TAF8在人类大脑发育中的作用。
