Precision mouse models of Yars/dominant intermediate Charcot‐Marie‐Tooth disease type C and Sptlc1/hereditary sensory and autonomic neuropathy type 1

• DOI: 10.1111/joa.13605
• Publication Date: 2021-12-08T00:50:28Z
• Authors: Timothy J. Hines; Abigail L. D. Tad...; Museer A. Lone; Courtney L. Hatton; Inseyah Bagasrawala; Morgane G. Stum; Kathy E. Miers; Thorsten Hornemann; Robert W. Burgess
• Keywords: Null allele; Heterozygote advantage

Abstract Animal models of neurodegenerative diseases such as inherited peripheral neuropathies sometimes accurately recreate the pathophysiology human disease, and genetic perturbations found in patients. Ideally, achieve both, but this is not always possible; nonetheless, are informative. Here we describe two animal neuropathy: mice with a mutation tyrosyl tRNA‐synthetase, Yars E196K , modeling dominant intermediate Charcot‐Marie‐Tooth disease type C (diCMTC), serine palmitoyltransferase long chain 1, Sptlc1 C133W hereditary sensory autonomic neuropathy 1 (HSAN1). develop disease‐relevant phenotypes including reduced motor performance nerve conduction velocities by 4 months age. Peripheral axons size, there no reduction axon number plasma neurofilament light levels increased. Unlike mutations, only show these homozygotes, or compound heterozygotes null allele, phenotype observed heterozygotes. The carry knockin allele anticipated increase 1‐deoxysphingolipids circulation variety tissues. They also have mild behavioral defects consistent HSAN1, do neurophysiological loss nerves epidermis hind paw tail. Thus, despite biochemical phenotype, strong phenotype. Surprisingly, were lethal heterozygous genotype studied corresponds to genetics seen humans. homozygous relevant imprecisely reproduce genetics, whereas precisely Despite shortcomings, both informative will be useful for future research.