Finding the genetic cause for inherited leukoencephalomyelopathy in Leonberger dogs using a genome wide association study approach.

Abstract

Leukoencephalomyelopathy (LEMP) is an inherited young-onset neurodegenerative disorder of the white matter of the central nervous system affecting both sexes. It is characterized by slowly worsening gait abnormalities, especially spontaneous knuckling, dragging of the paws and hypermetria (over-shooting) of the thoracic limbs. Affected dogs show gross lesions in the cervical spinal cord that may extend to the thoracic spinal cord as well as to the brain while peripheral nerve and muscle biopsies are unremarkable. Leonberger LEMP cases (n=12), healthy Leonberger controls over the age of 7 (n=72), and obligate carrier parents (n=2) were utilized. A genome wide association study was performed and revealed a possible locus, for LEMP, on chromosome (CFA) 18. An efficient mixed model association statistical test (EMMA) was used to correct for population structure arising from the relatedness of the cases. Haplotype analysis of LEMP affected dogs shows a 6Mb area of extended homozygosity for which the obligate carriers were either heterozygous or homozygous. Within this area is the candidate gene reelin (RELN) located, which is involved in the regulation of neuronal migration and positioning in the developing brain. The gene remains active in the adult brain. By genotyping 17 cases and 204 controls for single-nucleotide polymorphism (SNP) BICF2P192840 within the RELN gene, a strong association was confirmed. Linkage analysis is done for further validation of the LEMP loci. The search for a causative mutation with next generation and conventional Sanger DNA sequencing is on going. A comparable LEMP as in the Leonberger has been described in Rottweiler dogs. The associated SNP variants seen in Leonberger dogs were compared with those in affected and non-affected Rottweiler dogs to determine if the same genetic basis exists for LEMP in both breeds. No significant association has been found yet.