Solano Elaina, Foksinska Aleksandra, Crowder Camerron M
Department of Neurobiology, University of Alabama at Birmingham, Birmingham, AL, United States.
Hugh Kaul Precision Medicine Institute, University of Alabama at Birmingham, Birmingham, AL, United States.
Front Pediatr. 2024 Dec 16;12:1448793. doi: 10.3389/fped.2024.1448793. eCollection 2024.
RHOBTB2 is a member of the Rho GTPases subfamily of signaling proteins, known tumor suppressors whose loss of function and decreased expression is associated with cancer onset. Beyond its cancer-related role, RHOBTB2 is implicated in rare neurodevelopmental disorders, specifically -related disorders, recognized in 2018 as a subtype of developmental and epileptic encephalopathies (DEE). Common symptoms of these disorders include early-onset epilepsy, severe intellectual disability, microcephaly, and movement disorders. Few studies have investigated patient variants associated with -related disorders, and the impact of these variants on protein function remains unclear. Limited research suggests that the accumulation of RHOBTB2 in neural tissues contributes to the development of DEE. Similarly, preclinical studies indicate that missense variants near or in the BTB domain of RHOBTB2 result in decreased degradation of RHOBTB2 and the onset of DEE, whereas variants in the GTPase domain cause more variable neurodevelopmental symptoms, but do not impair proteasomal degradation of RHOBTB2. However, the exact pathophysiological mechanisms are unclear and may differ across variants. Current treatment approaches for individuals with -related DEE involve the use of antiseizure medications to decrease seizures; however, no treatments have been identified that address the other symptoms or the underlying pathophysiological mechanisms associated with these disorders. Overall, RHOBTB2 remains an understudied protein with limited information on its function and how it contributes to disease mechanisms. This review provides an overview of the current knowledge of RHOBTB2 function with an emphasis on its association with neurodevelopmental disorders through an analysis of preclinical studies and case reports that link individual variants with clinical features.
RHOBTB2是信号蛋白Rho GTPases亚家族的成员，是已知的肿瘤抑制因子，其功能丧失和表达降低与癌症发生有关。除了其与癌症相关的作用外，RHOBTB2还与罕见的神经发育障碍有关，特别是在2018年被确认为发育性和癫痫性脑病（DEE）亚型的相关疾病。这些疾病的常见症状包括早发性癫痫、严重智力残疾、小头畸形和运动障碍。很少有研究调查与相关疾病相关的患者变异，这些变异对蛋白质功能的影响仍不清楚。有限的研究表明，RHOBTB2在神经组织中的积累有助于DEE的发展。同样，临床前研究表明，RHOBTB2的BTB结构域附近或内部的错义变异导致RHOBTB2降解减少和DEE的发生，而GTPase结构域中的变异导致更多可变的神经发育症状，但不损害RHOBTB2的蛋白酶体降解。然而，确切的病理生理机制尚不清楚，可能因变异而异。目前针对患有相关DEE的个体的治疗方法包括使用抗癫痫药物来减少癫痫发作；然而，尚未确定能够解决其他症状或与这些疾病相关的潜在病理生理机制的治疗方法。总体而言，RHOBTB2仍然是一个研究不足的蛋白质，关于其功能以及它如何促成疾病机制的信息有限。本综述通过分析将个体变异与临床特征联系起来的临床前研究和病例报告，概述了目前关于RHOBTB2功能的知识，重点是其与神经发育障碍的关联。
