Dominant-Negative - Charcot-Marie-Tooth Disease

A dominant-negative variant produces a mutant protein that interferes with the function of its normal counterpart, lowering net activity through active disruption rather than simple absence. It is common where a protein oligomerizes or assembles into a complex, so the mutant subunit poisons the assembly. Because the mutant continues to interfere, adding back wild-type protein does not fully rescue. In CMT, dominant MFN2 alleles cause CMT2A through a dominant-negative effect.

See how the dominant-negative call is applied across subtypes in the CMT Variant Mechanisms Browser.

The Dorsal Root

A Name That Does Too Much Work

Jean-Martin Charcot's name appears throughout medicine, but nowhere does it create more confusion than in the foot. Learn why the CMT foot and Charcot neuroarthropathy, also known as Charcot foot, share a name yet differ in how they develop, appear, and are managed.

When Medicine Lost Its Compass

Evidence failed not because it was wrong, but because it was weaponized. I lived the downstream effects of that failure for more than a decade. This is what happens when medicine forgets that data always ends in a human being.

Error 404: Gene Not Found

CMT genetic testing often fails to identify the cause of the disease, even when comprehensive panels are used. Here, we discuss why this happens, what genetic tests can and cannot do, and why a negative result still matters.