De Hayr Lachlan, Blok Laura E R, Dias Kerith-Rae, Long Jingyi, Begemann Anaïs, Moir Robyn D, Willis Ian M, Mocera Martina, Siegel Gabriele, Steindl Katharina, Evans Carey-Anne, Zhu Ying, Zhang Futao, Field Michael, Ma Alan, Adès Lesley, Josephi-Taylor Sarah, Pfundt Rolph, Zaki Maha S, Tomoum Hoda, Gregor Anne, Laube Julia, Reis André, Maddirevula Sateesh, Hashem Mais O, Zweier Markus, Alkuraya Fowzan S, Maroofian Reza, Buckley Michael F, Gleeson Joseph G, Zweier Christiane, Coll-Tané Mireia, Koolen David A, Rauch Anita, Roscioli Tony, Schenck Annette, Harvey Robert J
School of Health, University of the Sunshine Coast, Maroochydore, QLD, Australia; National PTSD Research Centre, Thompson Institute, Birtinya, QLD, Australia.
Department of Human Genetics, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands.
Genet Med. 2025 Jan;27(1):101253. doi: 10.1016/j.gim.2024.101253. Epub 2024 Dec 5.
This study details a novel syndromic form of autosomal recessive intellectual disability resulting from recessive variants in GTF3C3, encoding a key component of the DNA-binding transcription factor IIIC, which has a conserved role in RNA polymerase III-mediated transcription.
Exome sequencing, minigene analysis, molecular modeling, RNA polymerase III reporter gene assays, and Drosophila knockdown models were utilized to characterize GTF3C3 variants.
Twelve affected individuals from 7 unrelated families were identified with homozygous or compound heterozygous missense variants in GTF3C3 including c.503C>T p.(Ala168Val), c.1268T>C p.(Leu423Pro), c.1436A>G p.(Tyr479Cys), c.2419C>T p.(Arg807Cys), and c.2420G>A p.(Arg807His). The cohort presented with intellectual disability, variable nonfamilial facial features, motor impairments, seizures, and cerebellar/corpus callosum malformations. Consistent with disruptions in intra- and intermolecular interactions observed in molecular modeling, RNA polymerase III reporter assays confirmed that the majority of missense variants resulted in a loss of function. Minigene analysis of the recurrent c.503C>T p.(Ala168Val) variant confirmed the introduction of a cryptic donor site into exon 4, resulting in mRNA missplicing. Consistent with the clinical features of this cohort, neuronal loss of Gtf3c3 in Drosophila induced seizure-like behavior, motor impairment, and learning deficits.
These findings confirm that GTF3C3 variants result in an autosomal recessive form of syndromic intellectual disability.
本研究详细描述了一种新型的常染色体隐性智力障碍综合征形式，其由GTF3C3基因的隐性变异导致，该基因编码DNA结合转录因子IIIC的一个关键组分，在RNA聚合酶III介导的转录过程中发挥保守作用。
利用外显子组测序、小基因分析、分子建模、RNA聚合酶III报告基因检测以及果蝇敲低模型来表征GTF3C3变异。
在7个不相关的家庭中鉴定出12名受影响个体，他们在GTF3C3基因中存在纯合或复合杂合错义变异，包括c.503C>T p.(Ala168Val)、c.1268T>C p.(Leu423Pro)、c.1436A>G p.(Tyr479Cys)、c.2419C>T p.(Arg807Cys)和c.2420G>A p.(Arg807His)。该队列中的患者表现出智力障碍、多样的非家族性面部特征、运动障碍、癫痫发作以及小脑/胼胝体畸形。与分子建模中观察到的分子内和分子间相互作用的破坏一致，RNA聚合酶III报告基因检测证实大多数错义变异导致功能丧失。对复发性c.503C>T p.(Ala168Val)变异的小基因分析证实在外显子4中引入了一个隐蔽的供体位点，导致mRNA错配剪接。与该队列的临床特征一致，果蝇中Gtf3c3的神经元缺失诱导了癫痫样行为、运动障碍和学习缺陷。
这些发现证实GTF3C3变异导致常染色体隐性形式的综合征性智力障碍。
