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

• DOI: 10.1111/jns.12588
• Publication Date: 2023-08-08T05:46:05Z
• Authors: A. L. D. Tadenev; C. L. Hatton; B. Pattavina; T. Mullins; R. Schneider; L. P. Bogdanik; Robert W. Burgess
• Keywords: Immunofluorescence; Connexin 32

Abstract Background Charcot–Marie–Tooth disease type 1X is caused by mutations in GJB1 , which the second most common gene associated with inherited peripheral neuropathy. The encodes connexin 32 (CX32), a gap junction protein expressed myelinating glial cells. X‐linked, and cause loss of function. Aims A large number disease‐associated variants have been identified, many result mistrafficking mislocalization protein. An existing knockout mouse lacking Gjb1 expression provides valid animal model CMT1X, but complete lack may not fully recapitulate mechanisms aberrant CX32 proteins. To better represent spectrum human CMT1X‐associated mutations, we generated new knockin model. Methods CRISPR/Cas9 genome editing was used to produce mice carrying R15Q mutation . In addition, identified allele an early frame shift codon 7 (del2). Mice were analyzed using clinically relevant molecular, histological, neurophysiological, behavioral assays. Results Both alleles detectable immunofluorescence Schwann cells, some properly localizing nodes Ranvier. However, both also neuropathy thinly myelinated demyelinated axons, as well degenerating regenerating predominantly distal motor nerves. Nerve conduction velocities only mildly reduced at later ages compound muscle action potential amplitudes reduced. Levels neurofilament light chain plasma elevated alleles. del2 onset ~3 months age, whereas had 5–6 suggesting milder performed comparably wild littermates accelerating rotarod grip strength tests neuromuscular performance. Interpretation We characterized two models CMT1X that will be useful for future mechanistic preclinical studies.