Phenotypic Heterogeneity in Human Genetic Diseases: Ultrasensitivity-Mediated Threshold Effects as a Unifying Molecular Mechanism

The review "Phenotypic heterogeneity in human genetic diseases: ultrasensitivity-mediated threshold effects as a unifying molecular mechanism" discusses the role of ultrasensitivity and threshold effects in explaining the variability in genetic diseases. The authors propose that phenotypic heterogeneity is driven by a threshold effect, where a phenotype may develop if the level or activity of a critical factor falls below a certain point. This threshold effect is influenced by ultrasensitivity, where the system is highly sensitive to small changes in the level or activity of a critical factor. The authors suggest three research strategies: identifying the primary mutation and modifier factors, identifying the Ultrasensitive Response Motif (URM) in the regulatory network, and finding ways to shift the system from an ultrasensitive state back to a stable healthy state. They also highlight the potential of manipulating thresholds for disease prevention or therapy. However, they acknowledge that this is a challenging task that requires experimental testing, the combination of 'omics data, and mathematical simulations.