Fralin Biomedical Research Institute at VTC, Roanoke, VA 24016, USA.
Department of Psychiatry, Virginia Tech Carilion School of Medicine, Roanoke, VA 24016, USA.
Cells. 2022 Mar 28;11(7):1131. doi: 10.3390/cells11071131.
Most human disease manifests as a result of tissue pathology, due to an underlying disease process (pathogenesis), rather than the acute loss of specific molecular function(s). Successful therapeutic strategies thus may either target the correction of a specific molecular function or halt the disease process. For the vast majority of brain diseases, clear etiologic and pathogenic mechanisms are still elusive, impeding the discovery or design of effective disease-modifying drugs. The development of valid animal models and their proper characterization is thus critical for uncovering the molecular basis of the underlying pathobiological processes of brain disorders. MICPCH (microcephaly and pontocerebellar hypoplasia) is a monogenic condition that results from variants of an X-linked gene, (calcium/calmodulin-dependent serine protein kinase). variants are associated with a wide range of clinical presentations, from lethality and epileptic encephalopathies to intellectual disabilities, microcephaly, and autistic traits. We have examined loss-of-function mutations in model organisms to simultaneously understand the pathogenesis of MICPCH and the molecular function/s of CASK. Our studies point to a highly complex relationship between the potential molecular function/s of and the phenotypes observed in model organisms and humans. Here we discuss the implications of our observations from the pathogenesis of MICPCH as a cautionary narrative against oversimplifying molecular interpretations of data obtained from genetically modified animal models of human diseases.
大多数人类疾病表现为组织病理学的结果，是由于潜在的疾病过程（发病机制），而不是特定分子功能的急性丧失。因此，成功的治疗策略可能靶向特定分子功能的纠正，或阻止疾病过程。对于绝大多数脑部疾病，明确的病因和发病机制仍难以捉摸，阻碍了有效疾病修饰药物的发现或设计。因此，开发有效的动物模型并对其进行适当的特征描述对于揭示脑部疾病潜在的病理生物学过程的分子基础至关重要。MICPCH（小头畸形和桥脑小脑发育不良）是一种单基因疾病，由 X 连锁基因（钙/钙调蛋白依赖性丝氨酸蛋白激酶）的变体引起。 变体与广泛的临床表现相关，从致死性和癫痫性脑病到智力障碍、小头畸形和自闭症特征。我们已经在模型生物中研究了功能丧失突变，以同时了解 MICPCH 的发病机制和 CASK 的分子功能。我们的研究指出了 潜在分子功能和模型生物以及人类中观察到的表型之间的高度复杂关系。在这里，我们讨论了从 MICPCH 的发病机制中获得的观察结果的意义，作为对从人类疾病的基因修饰动物模型中获得的数据进行分子解释过于简单化的警示。
