Gain-of-Function Properties of a Dynamin 2 Mutant Implicated in Charcot-Marie-Tooth Disease

Area of Science:

• Molecular biology
• Genetics
• Cell biology

Background:

• Dynamin 2 (DNM2) mutations cause autosomal-dominant Charcot-Marie-Tooth disease (CMT) and centronuclear myopathy (CNM).
• CMT mutations often impair DNM2's interaction with phosphatidylinositol (4,5) bisphosphate, suggesting loss-of-function.
• CNM mutations typically disrupt intramolecular interactions, leading to enhanced DNM2 self-assembly and GTPase activity, indicating gain-of-function.

Purpose of the Study:

• To investigate the molecular mechanisms of a specific CMT-linked DNM2 mutant (ΔDEE).
• To determine if CMT-associated DNM2 mutants can exhibit gain-of-function characteristics.
• To re-evaluate the distinct pathogenic mechanisms differentiating DNM2-dependent CMT and CNM.

Main Methods:

• Biochemical assays to analyze DNM2 polymer formation and GTPase activity.
• Analysis of tyrosine phosphorylation levels in wild-type and mutant DNM2.
• Characterization of the ΔDEE DNM2 mutant lacking residues 555-557.

Main Results:

• The CMT-linked ΔDEE DNM2 mutant forms polymers resistant to disassembly, similar to CNM mutants.
• The ΔDEE mutant displays enhanced GTPase activation, a gain-of-function characteristic.
• ΔDEE mutant shows significantly increased tyrosine phosphorylation compared to wild-type DNM2.

Conclusions:

• At least one CMT-associated DNM2 mutation can lead to gain-of-function effects.
• The distinction between loss-of-function (CMT) and gain-of-function (CNM) mechanisms in DNM2-related disorders may be less clear-cut.
• These findings necessitate a re-examination of the molecular basis underlying the pathogenic divergence between DNM2-dependent CMT and CNM.