The Non-Linear Path from Gene Dysfunction to Genetic Disease: Lessons from the MICPCH Mouse Model.
The Non-Linear Path from Gene Dysfunction to Genetic Disease: Lessons from the MICPCH Mouse Model.
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从基因功能障碍到遗传疾病的非线性路径：来自MICPCH小鼠模型的教训。
DOI：
10.3390/cells11071131
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发表时间：
2022-03-28
期刊：
影响因子：
6
通讯作者：
Srivastava S
中科院分区：
文献类型：
--
作者：
Mukherjee K;LaConte LEW;Srivastava S
大多数人类疾病表现为组织病理学的结果，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，成功的治疗策略可以针对特定分子功能的校正或停止疾病过程。对于绝大多数脑疾病，明确的病因和致病机制仍然是难以捉摸的，阻碍了有效的疾病修饰药物的发现或设计。因此，有效的动物模型的发展和他们的适当表征是至关重要的，揭示大脑疾病的潜在病理生物学过程的分子基础。MICPCH（小头畸形和脑桥小脑发育不全）是一种单基因疾病，由X连锁基因CASK（钙/钙调蛋白依赖性丝氨酸蛋白激酶）的变体引起。CASK变异与广泛的临床表现相关，从致死性和癫痫性脑病到智力残疾、小头畸形和自闭症特征。我们已经在模式生物中检测了CASK功能缺失突变，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，CASK的潜在分子功能与在模式生物和人类中观察到的表型之间存在高度复杂的关系。在这里，我们讨论的影响，我们的意见，从发病机制MICPCH作为一个警示性的叙述，对过度简化的分子解释的数据从转基因动物模型的人类疾病。
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, CASK (calcium/calmodulin-dependent serine protein kinase). CASK 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 CASK 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 CASK 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.
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影响因子：
4.4
作者：
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通讯作者：
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通讯作者：
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影响因子：
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作者：
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