Department of Biochemistry and Molecular Medicine, School of Medicine, University of California Davis, Sacramento, CA, 95817, USA.
Department of Pediatrics, School of Medicine, University of California Davis, Sacramento, CA, 95817, USA.
Metabolomics. 2024 Feb 28;20(2):31. doi: 10.1007/s11306-024-02088-0.
The chromosome 22q11.2 deletion syndrome (22q11.2DS) is characterized by a well-defined microdeletion and is associated with a wide range of brain-related phenotypes including schizophrenia spectrum disorders (SCZ), autism spectrum disorders (ASD), anxiety disorders and attention deficit disorders (ADHD). The typically deleted region in 22q11.2DS contains multiple genes which haploinsufficiency has the potential of altering the protein and the metabolic profiles.
Alteration in metabolic processes and downstream protein pathways during the early brain development may help to explain the increased prevalence of the observed neurodevelopmental phenotypes in 22q11.2DS. However, relatively little is known about the correlation of dysregulated protein/metabolite expression and neurobehavioral impairments in individuals who developed them over time.
In this study, we performed untargeted metabolic and proteomic analysis in plasma samples derived from 30 subjects including 16 participants with 22q11.2DS and 14 healthy controls (TD) enrolled in a longitudinal study, aiming to identify a metabolic and protein signature informing about the underlying mechanisms involved in disease development and progression. The metabolic and proteomic profiles were also compared between the participants with 22q11.2DS with and without various comorbidities, such as medical involvement, psychiatric conditions, and autism spectrum disorder (ASD) to detect potential changes among multiple specimens, collected overtime, with the aim to understand the basic underlying mechanisms involved in disease development and progression.
We observed a large number of statistically significant differences in metabolites between the two groups. Among them, the levels of taurine and arachidonic acid were significantly lower in 22q11.2DS compared to the TD group. In addition, we identified 16 proteins that showed significant changes in expression levels (adjusted P < 0.05) in 22q11.2DS as compared to TD, including those involved in 70 pathways such as gene expression, the PI3K-Akt signaling pathway and the complement system. Within participants with 22q11.2DS, no significant changes in those with and without medical or psychiatric conditions were observed.
To our knowledge, this is the first report on plasma metabolic and proteomic profiling and on the identification of unique biomarkers in 22q11.2DS. These findings may suggest the potential role of the identified metabolites and proteins as biomarkers for the onset of comorbid conditions in 22q11.2DS. Ultimately, the altered protein pathways in 22q11.2DS may provide insights of the biological mechanisms underlying the neurodevelopmental phenotype and may provide missing molecular outcome measures in future clinical trials to assess early-diagnosis treatment and the efficacy of response to targeted treatment.
22 号染色体长臂 11.2 区缺失综合征（22q11.2DS）的特征是明确的微缺失，并与广泛的与大脑相关的表型相关，包括精神分裂症谱系障碍（SCZ）、自闭症谱系障碍（ASD）、焦虑症和注意缺陷障碍（ADHD）。22q11.2DS 中典型缺失的区域包含多个基因，其单倍不足有可能改变蛋白质和代谢特征。
在早期大脑发育过程中代谢过程和下游蛋白途径的改变可能有助于解释在 22q11.2DS 中观察到的神经发育表型的患病率增加。然而，对于随着时间的推移而发展的个体中失调的蛋白质/代谢物表达与神经行为损伤之间的相关性，人们知之甚少。
在这项研究中，我们对来自 30 名参与者的血浆样本进行了非靶向代谢和蛋白质组学分析，其中包括 16 名患有 22q11.2DS 的参与者和 14 名健康对照（TD），这些参与者参加了一项纵向研究，旨在确定代谢和蛋白质特征，以了解参与疾病发展和进展的潜在机制。还比较了 22q11.2DS 参与者中存在和不存在各种合并症（如医疗介入、精神疾病和自闭症谱系障碍（ASD））之间的代谢和蛋白质谱，以检测随着时间的推移收集的多个样本中的潜在变化，旨在了解疾病发展和进展中涉及的基本潜在机制。
我们观察到两组之间代谢物的大量统计学显著差异。其中，与 TD 组相比，22q11.2DS 组的牛磺酸和花生四烯酸水平显著降低。此外，我们鉴定了 16 种在 22q11.2DS 中表达水平发生显著变化（调整后 P<0.05）的蛋白质，包括参与基因表达、PI3K-Akt 信号通路和补体系统等 70 种途径的蛋白质。在 22q11.2DS 参与者中，未观察到存在和不存在医疗或精神疾病的参与者之间有显著变化。
据我们所知，这是第一篇关于 22q11.2DS 血浆代谢组学和蛋白质组学分析以及鉴定独特生物标志物的报告。这些发现可能表明所鉴定的代谢物和蛋白质作为 22q11.2DS 合并症发病的潜在标志物的作用。最终，22q11.2DS 中改变的蛋白途径可能为神经发育表型的生物学机制提供见解，并为未来临床试验中评估早期诊断治疗和对靶向治疗的反应提供缺失的分子终点。
