A missense variant in PAOX in American Staffordshire Terriers with juvenile-onset polyneuropathy

Hereditary polyneuropathies in dogs mirror many features of human Charcot-Marie-Tooth (CMT) disease and offer valuable spontaneous models for discovery of genes' variants involved in this disorder. A juvenile-onset polyneuropathy (JOP) in American Staffordshire Terriers (ASTs) resembles CMT, with motor and sensory deficits, often accompanied by laryngeal paralysis. To identify the underlying genetic cause, we conducted a genome-wide association study (GWAS) with 24 affected and 53 control ASTs that identified a significant locus at the distal end of chromosome 28. Homozygosity mapping analysis further defined a critical interval spanning 11 protein-coding genes and whole-genome sequencing revealed a missense variant in the PAOX gene encoding polyamine oxidase (NC_049249.1:g.41474541G>A ), leading to a glycine-to-arginine substitution at a highly conserved residue, XP_038435135.1:p.(Gly382Arg). Genotypes at this variant were homozygous alternate in 96% of the affected dogs (n=53) and either homozygous reference or heterozygous in 336 unaffected ASTs; the mutant allele was not detected in any of 2519 genomes of other dog breeds. In silico predictions consistently supported its pathogenicity, and structural modeling suggested altered substrate binding. Although PAOX expression was preserved, proteomic profiling in affected nerve tissue revealed reduced levels of myelin-associated proteins, as well as dysregulation of mitochondrial and proteasomal pathways. Our findings establish this PAOX missense variant as the likely cause of JOP in ASTs and highlight the breed as a valuable large-animal model for studying inherited peripheral neuropathies. These results expand the spectrum of genes implicated in polyneuropathies and provide a basis for genetic testing and informed breeding strategies in ASTs.