Variable expression of MECP2, CDKL5, and FMR1 in the human brain: Implications for gene restorative therapies

• 成果类型: Article
• 署名作者: Zito, Antonino; Lee, Jeannie T.
• 署名单位: Harvard University; Harvard University Medical Affiliates; Massachusetts General Hospital; Harvard University; Harvard Medical School
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-15422
• DOI: 10.1073/pnas.2312757121
• 发表日期: 2024-02-27
• 关键词: cpg-binding protein-2; rett-syndrome; mouse model; deficiency; astrocytes; database; neurons; rnas; dysregulation; inactivation

摘要

MECP2, CDKL5, and FMR1 are three X- linked neurodevelopmental genes associated with Rett, CDKL5- , and fragile- X syndrome, respectively. These syndromes are char-acterized by distinct constellations of severe cognitive and neurobehavioral anomalies, reflecting the broad but unique expression patterns of each of the genes in the brain. As these disorders are not thought to be neurodegenerative and may be reversible, a major goal has been to restore expression of the functional proteins in the patient's brain. Strategies have included gene therapy, gene editing, and selective Xi- reactivation methodologies. However, tissue penetration and overall delivery to various regions of the brain remain challenging for each strategy. Thus, gaining insights into how much resto-ration would be required and what regions/cell types in the brain must be targeted for meaningful physiological improvement would be valuable. As a step toward addressing these questions, here we perform a meta-analysis of single-cell transcriptomics data from the human brain across multiple developmental stages, in various brain regions, and in multiple donors. We observe a substantial degree of expression variability for MECP2, CDKL5, and FMR1 not only across cell types but also between donors. The wide range of expression may help define a therapeutic window, with the low end delineating a minimum level required to restore physiological function and the high end inform-ing toxicology margin. Finally, the inter- cellular and inter- individual variability enable identification of co- varying genes and will facilitate future identification of biomarkers