RABGAP1是一种参与多种细胞和分子过程的GTP酶激活蛋白,包括有丝分裂,细胞迁移,囊泡贩运,和mTOR信号。没有已知的由RABGAP1中的变体引起的孟德尔疾病。
通过GeneMatcher,我们从3个不相关的家族中鉴定出5例患者,其在外显子组测序中发现RABGAP1基因具有纯合变异.我们建立了来自受影响个体及其父母的淋巴母细胞系,并进行了RNA测序和功能研究。产生Rabgap1敲除小鼠并进行表型分析。
我们报告了5例表现出共同特征的患者,包括全球发育迟缓/智力残疾,小头畸形,双侧感音神经性听力损失,和癫痫发作,以及重叠的变形特征。神经成像揭示了共同特征,包括延迟髓鞘形成,白质体积损失,脑室肿大,胼胝体变薄。患者细胞的功能分析显示mTOR信号下调和早期内体和溶酶体的异常定位。Rabgap1敲除小鼠表现出与患者队列相同的几个特征,包括小头畸形,胼胝体变薄,还有脑室肿大.
集体,我们的研究结果提供了一种由RABGAP1双等位基因功能缺失变异体引起的新型神经发育综合征的证据.
RABGAP1 is a GTPase-activating protein implicated in a variety of cellular and molecular processes, including mitosis, cell migration, vesicular trafficking, and mTOR signaling. There are no known Mendelian diseases caused by variants in RABGAP1.
Through GeneMatcher, we identified 5 patients from 3 unrelated families with homozygous variants in the RABGAP1 gene found on exome sequencing. We established lymphoblastoid cells lines derived from an affected individual and her parents and performed RNA sequencing and functional studies. Rabgap1 knockout mice were generated and phenotyped.
We report 5 patients presenting with a common constellation of features, including global developmental delay/intellectual disability, microcephaly, bilateral sensorineural hearing loss, and seizures, as well as overlapping dysmorphic features. Neuroimaging revealed common features, including delayed myelination, white matter volume loss, ventriculomegaly, and thinning of the corpus callosum. Functional analysis of patient cells revealed downregulated mTOR signaling and abnormal localization of early endosomes and lysosomes. Rabgap1 knockout mice exhibited several features in common with the patient cohort, including microcephaly, thinning of the corpus callosum, and ventriculomegaly.
Collectively, our results provide evidence of a novel neurodevelopmental syndrome caused by biallelic loss-of-function variants in RABGAP1.