Department of Molecular and Developmental Medicine, University of Siena, 53100 Siena, Italy;
Neonatal Intensive Care Unit, Azienda Ospedaliera Universitaria Senese, 53100 Siena, Italy;
Int J Mol Sci. 2021 Apr 19;22(8):4240. doi: 10.3390/ijms22084240.
Neuroprostanes, a family of non-enzymatic metabolites of the docosahexaenoic acid, have been suggested as potential biomarkers for neurological diseases. Objective biological markers are strongly needed in Rett syndrome (RTT), which is a progressive X-linked neurodevelopmental disorder that is mainly caused by mutations in the methyl-CpG binding protein 2 () gene with a predominant multisystemic phenotype. The aim of the study is to assess a possible association between mutations or RTT disease progression and plasma levels of 4()-4-F-neuroprostane (4-F-NeuroP) and 10()-10-F-neuroprostane (10-F-NeuroP) in typical RTT patients with proven gene mutation. Clinical severity and disease progression were assessed using the Rett clinical severity scale (RCSS) in n = 77 RTT patients. The 4-F-NeuroP and 10-F-NeuroP molecules were totally synthesized and used to identify the contents of the plasma of the patients. Neuroprostane levels were related to mutation category (i.e., early truncating, gene deletion, late truncating, and missense), specific hotspot mutations (i.e., R106W, R133C, R168X, R255X, R270X, R294X, R306C, and T158M), and disease stage (II through IV). Circulating 4-F-NeuroP and 10-F-NeuroP were significantly related to (i) the type of mutations where higher levels were associated to gene deletions ( ≤ 0.001); (ii) severity of common hotspot mutation (large deletions, R168X, R255X, and R270X); (iii) disease stage, where higher concentrations were observed at stage II ( ≤ 0.002); and (iv) deficiency in walking ( ≤ 0.0003). This study indicates the biological significance of 4-F-NeuroP and 10-F-NeuroP as promising molecules to mark the disease progression and potentially gauge genotype-phenotype associations in RTT.
神经前列腺素是二十二碳六烯酸的非酶代谢物家族，已被认为是神经退行性疾病的潜在生物标志物。在雷特综合征（RTT）中，迫切需要客观的生物学标志物。RTT 是一种进行性 X 连锁神经发育障碍，主要由甲基化 CpG 结合蛋白 2（）基因突变引起，主要表现为多系统表型。本研究的目的是评估 4()-4-F-神经前列腺素（4-F-NeuroP）和 10()-10-F-神经前列腺素（10-F-NeuroP）与已证实的 基因突变的典型 RTT 患者的 基因突变或 RTT 疾病进展之间的可能关联。在 n = 77 名 RTT 患者中，使用雷特临床严重程度评分（RCSS）评估临床严重程度和疾病进展。完全合成了 4-F-NeuroP 和 10-F-NeuroP 分子，并用于鉴定患者血浆中的含量。神经前列腺素水平与 突变类别（即早期截断、基因缺失、晚期截断和错义）、特定热点突变（即 R106W、R133C、R168X、R255X、R270X、R294X、R306C 和 T158M）和疾病阶段（II 期至 IV 期）相关。循环 4-F-NeuroP 和 10-F-NeuroP 与以下因素显著相关：（i）基因突变类型，较高水平与基因缺失相关（≤0.001）；（ii）常见热点突变的严重程度（大缺失、R168X、R255X 和 R270X）；（iii）疾病阶段，在 II 期观察到更高的浓度（≤0.002）；（iv）步行缺陷（≤0.0003）。本研究表明 4-F-NeuroP 和 10-F-NeuroP 作为有前途的分子具有生物学意义，可以标记疾病进展，并可能评估 RTT 中的基因型-表型相关性。
