Phenotypic heterogeneity in human genetic diseases: ultrasensitivity-mediated threshold effects as a unifying molecular mechanism

Journal of Biomedical Science

Review

Yueh-Lin Wu¹  Y. Henry Sun²  Ben-Yang Liao³ 

[1] Institute of Molecular and Genomic Medicine, National Health Research Institute, Zhunan, Miaoli, Taiwan;Division of Nephrology, Department of Internal Medicine, Wei-Gong Memorial Hospital, Miaoli, Taiwan;Division of Nephrology, Department of Internal Medicine, Taipei Medical University Hospital, Taipei, Taiwan;TMU Research Center of Urology and Kidney, Taipei Medical University, Taipei, Taiwan;Division of Nephrology, Department of Internal Medicine, Wan Fang Hospital, Taipei Medical University, Taipei City, Taiwan;Institute of Molecular and Genomic Medicine, National Health Research Institute, Zhunan, Miaoli, Taiwan;Institute of Molecular Biology, Academia Sinica, Taipei, Taiwan;Institute of Population Health Sciences, National Health Research Institute, Zhunan, Miaoli, Taiwan;

关键词: Phenotypic heterogeneity;    Penetrance;    Expressivity;    Pleiotropy;    Stochasticity;    Threshold;    Ultrasensitivity;    Ultrasensitive response motif (URM);    Network;    Edgetic mutation;   

DOI  :  10.1186/s12929-023-00959-7

 received in 2023-04-01, accepted in 2023-07-26,  发布年份 2023

来源: Springer

【 摘 要 】

Phenotypic heterogeneity is very common in genetic systems and in human diseases and has important consequences for disease diagnosis and treatment. In addition to the many genetic and non-genetic (e.g., epigenetic, environmental) factors reported to account for part of the heterogeneity, we stress the importance of stochastic fluctuation and regulatory network topology in contributing to phenotypic heterogeneity. We argue that a threshold effect is a unifying principle to explain the phenomenon; that ultrasensitivity is the molecular mechanism for this threshold effect; and discuss the three conditions for phenotypic heterogeneity to occur. We suggest that threshold effects occur not only at the cellular level, but also at the organ level. We stress the importance of context-dependence and its relationship to pleiotropy and edgetic mutations. Based on this model, we provide practical strategies to study human genetic diseases. By understanding the network mechanism for ultrasensitivity and identifying the critical factor, we may manipulate the weak spot to gently nudge the system from an ultrasensitive state to a stable non-disease state. Our analysis provides a new insight into the prevention and treatment of genetic diseases.

【 授权许可】

CC BY   
© The Author(s) 2023

【 图 表 】

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