Centre de génétique humaine, Université de Franche-Comté, Besançon, France.
Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Am J Hum Genet. 2023 Mar 2;110(3):499-515. doi: 10.1016/j.ajhg.2023.01.006. Epub 2023 Jan 31.
Telomere maintenance 2 (TELO2), Tel2 interacting protein 2 (TTI2), and Tel2 interacting protein 1 (TTI1) are the three components of the conserved Triple T (TTT) complex that modulates activity of phosphatidylinositol 3-kinase-related protein kinases (PIKKs), including mTOR, ATM, and ATR, by regulating the assembly of mTOR complex 1 (mTORC1). The TTT complex is essential for the expression, maturation, and stability of ATM and ATR in response to DNA damage. TELO2- and TTI2-related bi-allelic autosomal-recessive (AR) encephalopathies have been described in individuals with moderate to severe intellectual disability (ID), short stature, postnatal microcephaly, and a movement disorder (in the case of variants within TELO2). We present clinical, genomic, and functional data from 11 individuals in 9 unrelated families with bi-allelic variants in TTI1. All present with ID, and most with microcephaly, short stature, and a movement disorder. Functional studies performed in HEK293T cell lines and fibroblasts and lymphoblastoid cells derived from 4 unrelated individuals showed impairment of the TTT complex and of mTOR pathway activity which is improved by treatment with Rapamycin. Our data delineate a TTI1-related neurodevelopmental disorder and expand the group of disorders related to the TTT complex.
端粒维持 2 号（TELO2）、Tel2 相互作用蛋白 2（TTI2）和 Tel2 相互作用蛋白 1（TTI1）是保守的 Triple T（TTT）复合物的三个组成部分，通过调节 mTOR 复合物 1（mTORC1）的组装来调节磷脂酰肌醇 3-激酶相关蛋白激酶（PIKKs）的活性，包括 mTOR、ATM 和 ATR。TTT 复合物对于 ATM 和 ATR 在应对 DNA 损伤时的表达、成熟和稳定性至关重要。已经在具有中度至重度智力残疾（ID）、身材矮小、出生后小头畸形和运动障碍的个体中描述了 TELO2 和 TTI2 相关的双等位基因常染色体隐性（AR）脑病。我们展示了来自 9 个无关家庭的 11 名个体的临床、基因组和功能数据，这些个体在 TTI1 中存在双等位基因变异。所有个体均存在 ID，大多数存在小头畸形、身材矮小和运动障碍。在来自 4 个无关个体的 HEK293T 细胞系和成纤维细胞以及淋巴母细胞中进行的功能研究表明，TTT 复合物和 mTOR 通路活性受损，而雷帕霉素治疗可改善这种情况。我们的数据描绘了一种与 TTI1 相关的神经发育障碍，并扩展了与 TTT 复合物相关的疾病组。
