A Non-Synonymous Change in Latrophilin-3 Associated with Equine Degenerative Myeloencephalopathy

Equine Degenerative Myeloencephalopathy (EDM) is a neurological disease of young horses that is suspected to be inherited. This condition results in progressive development of symmetric ataxia predominantly in the hind limbs. EDM is the result of degeneration of the motor neurons in the spinal cord. There is no treatment for this disease, affected horses are frequently euthanized and diagnosis confirmed at necropsy. Variants of several candidate genes have been excluded as the cause of EDM. Two diagnosed cases from a family of Caspian horses were submitted for genetic evaluation and a run of homozygosity was found on E.caballus chromosome 3 through the Autozygosity by Difference method. This region contains only one gene, Latrophilin-3 (LPHN3). LPHN3 is a member of the latrophilin subfamily of G-protein coupled receptors and had been associated with Attention Deficit/Hyperactivity Disorder (ADHD) in humans and hyperactive motor function in mice and zebrafish. The predicted exons of LPHN3 in the two cases and one control were sequenced and analyzed for sequence differences between the affected and unaffected phenotypes. A non-synonymous SNP was discovered in exon 20 of the expected coding region. Here we report investigation of the frequency for this mutation in Caspian and Shetland relatives (0.21) of the two initial cases, as well as unrelated horses from similar breeds, Arabians (0.02), American Miniatures (0.09), and Shetlands (0.10). No homozygotes were found outside the case family. This study suggests that the SNP in exon 20 of LPHN3 may be a factor in causing Caspian Horse EDM.