Structural insights into Charcot-Marie-Tooth disease-linked mutations in human GDAP1

Area of Science:

• Biochemistry
• Structural Biology
• Genetics

Background:

• Charcot-Marie-Tooth disease (CMT) is a common inherited peripheral neuropathy.
• Mutations in ganglioside-induced differentiation-associated protein 1 (GDAP1) cause CMT types 4A and 2K.
• The molecular basis of GDAP1-linked CMT remains unclear.

Purpose of the Study:

• To investigate the biochemical and structural properties of GDAP1 variants associated with CMT2K.
• To elucidate the structural mechanisms underlying GDAP1-linked CMT.

Main Methods:

• X-ray crystallography of GDAP1 variants.
• Analysis of protein structure, stability, and interaction networks.
• Biochemical characterization of disease-associated mutations (H123R, R120W).

Main Results:

• GDAP1 variants (H123R, R120W) showed reduced thermal stability despite near-normal structure.
• Mutations disrupt an interaction network involving helices ⍺3, ⍺6, and ⍺7.
• A hinge in helix ⍺6, crucial for flexibility, is affected by mutations.

Conclusions:

• CMT pathogenesis may involve the disruption of intra- and intermolecular interaction networks in GDAP1.
• Altered GDAP1 structure and stability lead to impaired motor and sensory neuron function.
• Understanding these structural changes provides insight into GDAP1-linked CMT etiology.