The NeflE397K mouse model demonstrates muscle pathology and motor function deficits consistent with CMT2E

Area of Science:

• Neuroscience
• Genetics
• Neuromuscular Disorders

Background:

• Charcot-Marie-Tooth (CMT) disease is a group of inherited peripheral neuropathies affecting 1 in 2500 individuals.
• CMT type 2E arises from mutations in the neurofilament light (NEFL) gene, leading to progressive motor and sensory dysfunction.
• Existing mouse models partially recapitulate CMT2E, necessitating improved models for research.

Purpose of the Study:

• To characterize novel mouse models (NeflE397K) for Charcot-Marie-Tooth type 2E.
• To investigate motor function, muscle pathology, and respiratory changes in these models.
• To establish a clinically relevant model for evaluating potential therapeutics.

Main Methods:

• Generation of two orthologous NEFL E396K mutations in C57BL/6J mice, named NeflE397K.
• Longitudinal assessment of motor coordination, muscle characteristics, and breathing patterns up to 12 months of age.
• Comparative analysis between heterozygous (Nefl+/E397K) and homozygous (NeflE397K/E397K) mutant mice.

Main Results:

• Nefl+/E397K and NeflE397K/E397K mice displayed progressive motor deficits and muscle weakness.
• Alterations in muscle fiber size, diameter, and composition were observed as the disease progressed.
• Mutant mice exhibited increased apneas and erratic breathing patterns, particularly under respiratory challenge.

Conclusions:

• The NeflE397K mouse models accurately recapitulate key aspects of CMT type 2E.
• These models demonstrate progressive neuromuscular and respiratory phenotypes.
• The NeflE397K models provide a robust platform for preclinical therapeutic testing in CMT2E.