Agarwal Mudit, Johnston Michael V, Stafstrom Carl E
All India Institute of Medical Sciences, New Delhi, India.
Department of Neurology and Developmental Medicine, The Kennedy Krieger Institute, Baltimore, MD, United States.
Int J Dev Neurosci. 2019 Nov;78:65-76. doi: 10.1016/j.ijdevneu.2019.08.003. Epub 2019 Aug 24.
SYNGAP1 is a gene that encodes the cytosolic protein SYNGAP1 (SYNaptic GTPase Activating Protein), an essential component of the postsynaptic density at excitatory glutamatergic neurons. SYNGAP1 plays critical roles in synaptic development, structure, function, and plasticity. Mutations in SYNGAP1 result in a neurodevelopmental disorder termed Mental retardation-type 5 (MRD5, OMIM #612621) with a phenotype consisting of intellectual disability, motor impairments, and epilepsy, attesting to the importance of this protein for normal brain development. Here we review the clinical and pathophysiological aspects of SYNGAP1 mutations with a focus on their effect on synaptogenesis, neural circuit function, and cellular plasticity. We conclude by comparing the molecular pathogenesis of SYNGAP1 mutations with those of another neurodevelopmental disorder that affects dendritic function and cellular plasticity, fragile X syndrome. Insights into the molecular similarities and differences underlying these disorders could lead to rationale therapy development.
SYNGAP1是一种编码胞质蛋白SYNGAP1（突触GTP酶激活蛋白）的基因，该蛋白是兴奋性谷氨酸能神经元突触后致密物的重要组成部分。SYNGAP1在突触发育、结构、功能和可塑性方面发挥着关键作用。SYNGAP1突变会导致一种名为5型智力发育迟缓（MRD5，OMIM #612621）的神经发育障碍，其表型包括智力残疾、运动障碍和癫痫，这证明了这种蛋白质对正常大脑发育的重要性。在这里，我们回顾SYNGAP1突变的临床和病理生理学方面，重点关注它们对突触发生、神经回路功能和细胞可塑性的影响。我们通过比较SYNGAP1突变与另一种影响树突功能和细胞可塑性的神经发育障碍——脆性X综合征的分子发病机制来得出结论。对这些疾病潜在分子异同的深入了解可能会推动合理治疗方法的发展。
