Covarelli Jasmine, Vinciarelli Elisa, Mirarchi Alessandra, Prontera Paolo, Arcuri Cataldo
Department of Medicine and Surgery, University of Perugia, Piazza L. Severi 1, 06132 Perugia, Italy.
Medical Genetics and Rare Disease Unit, Maternal-Infantile Department, S. Maria della Misericordia Hospital, 06132 Perugia, Italy.
Int J Mol Sci. 2025 Jul 11;26(14):6667. doi: 10.3390/ijms26146667.
Haploinsufficiency disorders are genetic diseases caused by reduced gene expression, leading to developmental, metabolic, and tumorigenic abnormalities. The dosage-sensitive Retinoic Acid Induced 1 () gene, located within the 17p11.2 region, is central to the core features of Smith--Magenis syndrome (SMS) and Potocki--Lupski syndrome (PTLS), caused by the reciprocal microdeletions and microduplications of this region, respectively. SMS and PTLS present contrasting phenotypes. SMS is characterized by severe neurobehavioral manifestations, sleep disturbances, and metabolic abnormalities, and PTLS shows milder features. Here, we detail the molecular functions of in its wild-type and haploinsufficiency conditions (RAI1+/-), as studied in animal and cellular models. RAI1 acts as a transcription factor critical for neurodevelopment and synaptic plasticity, a chromatin remodeler within the Histone 3 Lysine 4 (H3K4) writer complex, and a regulator of faulty 5'-capped pre-mRNA degradation. Alterations of RAI1 functions lead to synaptic scaling and transcriptional dysregulation in neural networks. This review highlights key molecular mechanisms of RAI1, elucidating its role in the interplay between genetics and phenotypic features and summarizes innovative therapeutic approaches for SMS. These data provide a foundation for potential therapeutic strategies targeting RAI1, its mRNA products, or downstream pathways.
单倍剂量不足疾病是由基因表达减少引起的遗传性疾病，会导致发育、代谢和致瘤异常。位于17p11.2区域的剂量敏感视黄酸诱导1（RAI1）基因，分别是由该区域的相互微缺失和微重复引起的史密斯-马吉尼斯综合征（SMS）和波托基-卢斯基综合征（PTLS）核心特征的关键所在。SMS和PTLS呈现出截然不同的表型。SMS的特征是严重的神经行为表现、睡眠障碍和代谢异常，而PTLS的特征则较为轻微。在此，我们详细阐述了在动物和细胞模型中所研究的RAI1在其野生型和单倍剂量不足状态（RAI1+/-）下的分子功能。RAI1作为一种对神经发育和突触可塑性至关重要的转录因子，是组蛋白3赖氨酸4（H3K4）书写复合物中的染色质重塑因子，也是有缺陷的5'-帽状前体mRNA降解的调节因子。RAI1功能的改变会导致神经网络中的突触缩放和转录失调。本综述强调了RAI1的关键分子机制，阐明了其在遗传学与表型特征相互作用中的作用，并总结了针对SMS的创新治疗方法。这些数据为针对RAI1及其mRNA产物或下游途径的潜在治疗策略奠定了基础。
