同源基因GTPBP1和GTPBP2编码GTP结合蛋白1和2,它们与核糖体稳态有关。GTPBP2中的致病变体最近被证明是神经退行性或神经发育障碍(NDD)的超罕见原因。直到现在,没有人类表型与GTPBP1相关。这里,我们描述了携带双等位基因GTPBP1变异体的个体,这些变异体表现出与GTPBP2相同的表型,并表征了GTP结合蛋白(1/2)相关疾病的总体谱.在这项研究中,通过全外显子组(WES)或全基因组(WGS)测序研究了来自16个具有不同NDD和综合征面部特征的家庭的20个人。为了评估所识别的遗传变异的功能影响,半定量PCR,westernblot,在受影响个体的成纤维细胞中进行核糖体谱分析。我们还研究了降低果蝇果蝇中人类GTPBP1/2的直系同源CG2017表达的效果。具有双等位基因GTPBP1或GTPBP2变体的个体表现为小头畸形,严重的神经发育障碍,病理性颅面特征,和外胚层缺陷。视力和/或听力异常,进行性痉挛,choreothetoid运动,难治性癫痫,脑萎缩是该综合征核心表型的一部分。细胞系研究鉴定了疾病相关变体的功能丧失(LoF)影响,但对核糖体谱没有显著异常。CG2017同工型表达降低与果蝇的运动障碍有关。总之,双等位基因GTPBP1和GTPBP2LoF变体导致相同的,独特的神经发育综合征。突变CG2017基因敲除果蝇表现出运动障碍,强调GTP结合蛋白在跨物种中枢神经系统发育中的保守作用。
The homologous genes GTPBP1 and
GTPBP2 encode GTP-binding proteins 1 and 2, which are involved in ribosomal homeostasis. Pathogenic variants in
GTPBP2 were recently shown to be an ultra-rare cause of neurodegenerative or neurodevelopmental disorders (NDDs). Until now, no human phenotype has been linked to GTPBP1. Here, we describe individuals carrying bi-allelic GTPBP1 variants that display an identical phenotype with
GTPBP2 and characterize the overall spectrum of GTP-binding protein (1/2)-related disorders. In this study, 20 individuals from 16 families with distinct NDDs and syndromic facial features were investigated by whole-exome (WES) or whole-genome (WGS) sequencing. To assess the functional impact of the identified genetic variants, semi-quantitative PCR, western blot, and ribosome profiling assays were performed in fibroblasts from affected individuals. We also investigated the effect of reducing expression of CG2017, an ortholog of human GTPBP1/2, in the fruit fly Drosophila melanogaster. Individuals with bi-allelic GTPBP1 or
GTPBP2 variants presented with microcephaly, profound neurodevelopmental impairment, pathognomonic craniofacial features, and ectodermal defects. Abnormal vision and/or hearing, progressive spasticity, choreoathetoid movements, refractory epilepsy, and brain atrophy were part of the core phenotype of this syndrome. Cell line studies identified a loss-of-function (LoF) impact of the disease-associated variants but no significant abnormalities on ribosome profiling. Reduced expression of CG2017 isoforms was associated with locomotor impairment in Drosophila. In conclusion, bi-allelic GTPBP1 and
GTPBP2 LoF variants cause an identical, distinct neurodevelopmental syndrome. Mutant CG2017 knockout flies display motor impairment, highlighting the conserved role for GTP-binding proteins in CNS development across species.