Carapito Raphael, Molitor Anne, Pavinato Lisa, Skeyni Alaa, Lambert Magalie, Pichot Angélique, Jiang Jiuhong, Spinnhirny Perrine, Zimmermann Lucie, Boucher Philippe, Chung Clara W T, Elserafy Noha, Blair Edward M, Li Dong, Elisabeth Bhoj, Kotzaeridou Urania, Karch Stephanie, Wagner Matias, Lunsing Roelineke J, Pfundt Rolph, Boycott Kym M, Bruel Ange-Line, Mau-Them Frédéric Tran, Moutton Sébastien, Conti Valerio, Mei Davide, Cetica Valentina, Guerrini Renzo, Brunet Theresa, Rump Patrick, Mussa Alessandro, Brusco Alfredo, Lemire Gabrielle, de Vries Bert B A, Miao Zhichao, Isidor Bertrand, Bahram Seiamak
Laboratoire d'ImmunoRhumatologie Moléculaire, plateforme GENOMAX, INSERM UMR_S 1109, Faculté de Médecine, Fédération Hospitalo-Universitaire OMICARE, Fédération de Médecine Translationnelle de Strasbourg (FMTS), Institut Thématique Interdisciplinaire TRANSPLANTEX NG, Université de Strasbourg, 4 rue Kirschleger, 67085, Strasbourg, France.
Service d'Immunologie Biologique, Plateau Technique de Biologie, Pôle de Biologie, Nouvel Hôpital Civil, 1 place de l'Hôpital, 67091, Strasbourg, France.
Eur J Hum Genet. 2024 Dec 30. doi: 10.1038/s41431-024-01774-w.
RICTOR is a key component of the mTORC2 signaling complex which is involved in the regulation of cell growth, proliferation and survival. RICTOR is highly expressed in neurons and is necessary for brain development. Here, we report eight unrelated patients presenting with intellectual disability and/or development delay and carrying variants in the RICTOR gene. The phenotypic presentation is diverse with associated features including growth failure, feeding difficulties, abnormal behavior, seizure, hypertonia, brain anomalies and various other congenital organ and skeletal malformations. All patients carried de novo or heterozygous variants inherited from one affected parent, including three missense variants, four loss-of-function variants and one 3 kb deletion encompassing RICTOR. The mTORC2 pathway was hyperactivated in a patient's fibroblasts carrying a missense variant, while the expression of RICTOR remained unchanged, indicating a gain-of-function mechanism. RNA sequencing on RICTOR knock-out mouse embryonic fibroblasts confirmed the potential role of RICTOR in neuronal cell development.
RICTOR是mTORC2信号复合物的关键组成部分，参与细胞生长、增殖和存活的调节。RICTOR在神经元中高度表达，是大脑发育所必需的。在此，我们报告了8例无关患者，他们患有智力残疾和/或发育迟缓，且RICTOR基因存在变异。其表型表现多样，伴有生长发育迟缓、喂养困难、行为异常、癫痫、张力亢进、脑畸形以及各种其他先天性器官和骨骼畸形等相关特征。所有患者均携带从头突变或从一位患病父母遗传而来的杂合变异，包括3个错义变异、4个功能丧失变异和一个包含RICTOR的3 kb缺失。在一名携带错义变异的患者成纤维细胞中，mTORC2通路被过度激活，而RICTOR的表达保持不变，表明存在功能获得机制。对RICTOR基因敲除的小鼠胚胎成纤维细胞进行RNA测序，证实了RICTOR在神经元细胞发育中的潜在作用。
