Department of Molecular Biology, Massachusetts General Hospital, Boston, MA, USA; Department of Genetics, The Blavatnik Institute, Harvard Medical School, Boston, MA, USA; Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology, Barcelona, Spain; Universitat Pompeu Fabra (UPF), Barcelona, Spain.
Department of Molecular Biology, Massachusetts General Hospital, Boston, MA, USA; Department of Genetics, The Blavatnik Institute, Harvard Medical School, Boston, MA, USA.
Trends Genet. 2022 Sep;38(9):920-943. doi: 10.1016/j.tig.2022.01.007. Epub 2022 Mar 2.
The human X-chromosome harbors only 4% of our genome but carries over 20% of genes associated with intellectual disability. Given that they inherit only one X-chromosome, males are more frequently affected by X-linked neurodevelopmental genetic disorders than females. However, despite inheriting two X-chromosomes, females can also be affected because X-chromosome inactivation enables only one of two X-chromosomes to be expressed per cell. For Rett syndrome and similar X-linked disorders affecting females, disease-specific treatments have remained elusive. However, a cure may be found within their own cells because every sick cell carries a healthy copy of the affected gene on the inactive X (Xi). Therefore, selective Xi reactivation may be a viable approach that would address the root cause of various X-linked disorders. Here, we discuss Rett syndrome and compare current approaches in the pharmaceutical pipeline to restore MECP2 function. We then focus on Xi reactivation and review available methods, lessons learned, and future directions.
人类 X 染色体仅携带我们基因组的 4%，但却携带了超过 20%与智力障碍相关的基因。由于男性仅继承了一条 X 染色体，因此与 X 连锁神经发育遗传疾病相关的疾病比女性更为常见。然而，尽管女性继承了两条 X 染色体，但她们也可能受到影响，因为 X 染色体失活使得每个细胞中只能表达两条 X 染色体中的一条。对于雷特综合征和类似的影响女性的 X 连锁疾病，特定疾病的治疗方法仍然难以捉摸。然而，治愈的方法可能就在她们自己的细胞中，因为每个患病细胞的失活 X（Xi）上都携带了受影响基因的健康副本。因此，选择性的 Xi 重新激活可能是一种可行的方法，可以解决各种 X 连锁疾病的根本原因。在这里，我们讨论雷特综合征，并比较目前药物研发管道中恢复 MECP2 功能的方法。然后，我们将重点放在 Xi 重新激活上，并回顾现有的方法、经验教训和未来的方向。
