Department of Biochemistry and Molecular Medicine, School of Medicine, University of California, Davis, Davis, CA 95616, USA.
Medical Investigation of Neurodevelopmental Disorders (MIND) Institute, UC Davis Health, Sacramento, CA 95817, USA.
Genes (Basel). 2024 Mar 13;15(3):356. doi: 10.3390/genes15030356.
Fragile X syndrome (FXS) is the most common heritable cause of intellectual disability and autism spectrum disorder. The syndrome is often caused by greatly reduced or absent protein expression from the () gene due to expansion of a 5'-non-coding trinucleotide (CGG) element beyond 200 repeats (full mutation). To better understand the complex relationships among allelotype, methylation status, mRNA expression, and protein (FMRP) levels, FMRP was quantified in peripheral blood mononuclear cells for a large cohort of FXS ( = 154) and control ( = 139) individuals using time-resolved fluorescence resonance energy transfer. Considerable size and methylation mosaicism were observed among individuals with FXS, with FMRP detected only in the presence of such mosaicism. No sample with a minimum allele size greater than 273 CGG repeats had significant levels of FMRP. Additionally, an association was observed between mRNA and FMRP levels in FXS samples, predominantly driven by those with the lowest FMRP values. This study underscores the complexity of allelotypes and FMRP expression and prompts a reevaluation of FXS therapies aimed at reactivating large full mutation alleles that are likely not capable of producing sufficient FMRP to improve cognitive function.
脆性 X 综合征 (FXS) 是智力残疾和自闭症谱系障碍最常见的遗传性病因。该综合征通常由于 5'非编码三核苷酸 (CGG) 元件扩展超过 200 个重复（完全突变）而导致 () 基因的蛋白表达大大减少或缺失。为了更好地理解等位基因型、甲基化状态、mRNA 表达和 蛋白 (FMRP) 水平之间的复杂关系，使用时间分辨荧光共振能量转移技术在大量 FXS（= 154）和对照（= 139）个体的外周血单核细胞中定量了 FMRP。在 FXS 个体中观察到相当大的大小和甲基化镶嵌现象，只有在存在这种镶嵌现象的情况下才能检测到 FMRP。没有最小等位基因大小大于 273 CGG 重复的样本具有显著水平的 FMRP。此外，在 FXS 样本中观察到 mRNA 和 FMRP 水平之间存在关联，主要由那些 FMRP 值最低的样本驱动。这项研究强调了 等位基因型和 FMRP 表达的复杂性，并促使重新评估旨在重新激活可能无法产生足够 FMRP 以改善认知功能的大完全突变等位基因的 FXS 疗法。
