Division of Clinical and Metabolic Genetics, The Hospital for Sick Children, Toronto, Ontario, Canada.
Division of Clinical and Metabolic Genetics, The Hospital for Sick Children, Toronto, Ontario, Canada; Program in Genetics and Genome Biology, Hospital for Sick Children, Toronto, Ontario, Canada.
Genet Med. 2022 Nov;24(11):2399-2407. doi: 10.1016/j.gim.2022.07.024. Epub 2022 Sep 9.
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.
RABGAP1 是一种 GTP 酶激活蛋白，涉及多种细胞和分子过程，包括有丝分裂、细胞迁移、囊泡运输和 mTOR 信号转导。目前尚无已知的由 RABGAP1 变异引起的孟德尔疾病。
通过 GeneMatcher，我们在 3 个无关家庭的 5 名患者中发现了外显子组测序中发现的 RABGAP1 基因的纯合变异。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。生成了 Rabgap1 敲除小鼠并进行了表型分析。
我们报告了 5 名患者具有共同的特征组合，包括全面发育迟缓/智力残疾、小头畸形、双侧感觉神经性听力损失和癫痫发作，以及重叠的畸形特征。神经影像学显示出共同的特征，包括髓鞘形成延迟、白质体积减少、脑室扩大和胼胝体变薄。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的几个共同特征，包括小头畸形、胼胝体变薄和脑室扩大。
总之，我们的结果提供了证据，证明 RABGAP1 的双等位基因功能丧失变异导致了一种新的神经发育综合征。
