Characterization of a novel zebrafish model of MTMR5-associated CMT4B3

Biallelic loss of expression/function variants in MTMR5 cause the inherited peripheral neuropathy Charcot-Marie-Tooth (CMT) Type 4B3. There is an incomplete understanding of the disease pathomechanism(s) underlying CMT4B3, and despite its severe clinical presentation, currently no disease modifying therapies. A key barrier to the study of CMT4B3 is the lack of pre-clinical models that recapitulate the clinical and pathologic features of the disease. To address this barrier, we generated a zebrafish CRISPR/Cas9 mutant line with a full gene deletion of mtmr5. Resulting homozygous deletion zebrafish are born at normal Mendelian ratios and have preserved motor function. However, starting by 14 day-post-fertilization, mutant zebrafish develop obvious morphometric changes in head size and brain volume. These changes are accompanied at the pathological level by abnormal axon outgrowths and by the presence of dysmyelination, changes reminiscent of the nerve pathology in human CMT4B3. Overall, our mtmr5 zebrafish mirror genetic, clinical, and pathologic features of human CMT4B3. As such, it represents a first pre-clinical model to phenocopy the disease, and an ideal tool for future studies on disease pathomechanism(s) and therapy development. Summary StatementWe created a novel zebrafish mtmr5/sbf1 mutant model of Charcot-Marie-Tooth Type 4B3 that recapitulates key features of the human disorder and provides the first in vivo model for therapy development.