Two new mouse models of Gjb1-associated Charcot-Marie-Tooth disease type 1X

Area of Science:

• Genetics and Genomics
• Neuroscience
• Animal Models

Background:

• Charcot-Marie-Tooth disease type 1X (CMT1X) is an inherited peripheral neuropathy caused by mutations in the GJB1 gene, encoding connexin 32 (CX32).
• Existing GJB1 knockout models do not fully represent the spectrum of human CMT1X mutations, which often involve aberrant protein function rather than complete absence.

Observation:

• CRISPR/Cas9 genome editing generated GJB1 knockin mice with R15Q and early frame-shift (del2) mutations.
• Mice were assessed using molecular, histological, neurophysiological, and behavioral analyses.

Findings:

• Both GJB1 mutations resulted in peripheral neuropathy, characterized by thinly myelinated, demyelinated, and degenerating/regenerating axons.
• Elevated plasma neurofilament light chain levels were observed, with varying onset ages for the two mutations (del2 at ~3 months, R15Q at 5-6 months).
• Mild reductions in nerve conduction velocities and no reduction in compound muscle action potential amplitudes were noted; neuromuscular performance was comparable to wild-type.

Implications:

• These novel mouse models accurately reflect aspects of CMT1X pathology and disease progression.
• They provide valuable tools for investigating CMT1X disease mechanisms and evaluating preclinical therapeutic strategies.