A spontaneous dog model for a human sensory neuropathy: identification of a mutation in the upstream region of a neurotrophic factor

Abstract

In this study, we sought the genetic cause of self-mutilation syndrome in sporting dogs, which corresponds to human Hereditary Sensory and Autonomic Neuropathies (HSAN). We have identified a genetic mutation upstream of the gene encoding Glial cell line-Derived Neurotrophic Factor (GDNF). This mutation is responsible for insensitivity to pain in four sporting dog breeds and it perfectly segregates with the disease in 250 sporting dogs of known clinical status. Moreover, it was not found in any of the 900 unaffected dogs from 130 different breeds. Since this mutation is localized in a long non-coding RNA, we performed an in-depth analysis of the genomic region (locus) as well as gene expression analyses to understand its role in the pathophysiology of the disease. Thus, in addition to the discovery of a novel candidate gene for HSAN in humans, we propose a transcriptional regulation mechanism based on a “partnership” between GDNF and a long non-coding RNA (lncRNA).