van der Laan Liselot, Ten Voorde Nicky, Mannens Marcel M A M, Henneman Peter
Department of Human Genetics, Amsterdam UMC, Amsterdam, Netherlands.
Amsterdam Reproduction and Development, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, Netherlands.
Front Mol Neurosci. 2024 Jul 29;17:1446686. doi: 10.3389/fnmol.2024.1446686. eCollection 2024.
Mendelian disorders, arising from pathogenic variations within single genetic loci, often manifest as neurodevelopmental disorders (NDDs), affecting a significant portion of the pediatric population worldwide. These disorders are marked by atypical brain development, intellectual disabilities, and various associated phenotypic traits. Genetic testing aids in clinical diagnoses, but inconclusive results can prolong confirmation processes. Recent focus on epigenetic dysregulation has led to the discovery of DNA methylation signatures, or episignatures, associated with NDDs, accelerating diagnostic precision. Notably, TRIP12 and USP7, genes involved in the ubiquitination pathway, exhibit specific episignatures. Understanding the roles of these genes within the ubiquitination pathway sheds light on their potential influence on episignature formation. While TRIP12 acts as an E3 ligase, USP7 functions as a deubiquitinase, presenting contrasting roles within ubiquitination. Comparison of phenotypic traits in patients with pathogenic variations in these genes reveals both distinctions and commonalities, offering insights into underlying pathophysiological mechanisms. This review contextualizes the roles of TRIP12 and USP7 within the ubiquitination pathway, their influence on episignature formation, and the potential implications for NDD pathogenesis. Understanding these intricate relationships may unveil novel therapeutic targets and diagnostic strategies for NDDs.
孟德尔疾病由单个基因座内的致病变异引起，常表现为神经发育障碍（NDDs），影响全球相当一部分儿科人群。这些疾病的特征是非典型脑发育、智力残疾以及各种相关的表型特征。基因检测有助于临床诊断，但不确定的结果可能会延长确诊过程。最近对表观遗传失调的关注导致发现了与NDDs相关的DNA甲基化特征，即表观特征，从而提高了诊断精度。值得注意的是，参与泛素化途径的TRIP12和USP7基因表现出特定的表观特征。了解这些基因在泛素化途径中的作用有助于揭示它们对表观特征形成的潜在影响。虽然TRIP12作为一种E3连接酶起作用，但USP7作为一种去泛素化酶起作用，在泛素化过程中呈现出相反的作用。对这些基因存在致病变异的患者的表型特征进行比较，揭示了差异和共性，为潜在的病理生理机制提供了见解。本综述阐述了TRIP12和USP7在泛素化途径中的作用、它们对表观特征形成的影响以及对NDD发病机制的潜在影响。了解这些复杂的关系可能会揭示NDDs的新治疗靶点和诊断策略。
