An Inversion Disrupting FAM134B Is Associated with Sensory Neuropathy in the Border Collie Dog Breed

Abstract

Sensory neuropathy in the Border Collie is a severe neurological disorder caused by the degeneration of sensory and, to a lesser extent, motor nerve cells with clinical signs starting between 2 and 7 months of age. Using a genome-wide association study approach with three cases and 170 breed matched controls, a suggestive locus for sensory neuropathy was identified that was followed up using a genome sequencing approach. An inversion disrupting the candidate gene FAM134B was identified. Genotyping of additional cases and controls and RNAseq analysis provided strong evidence that the inversion is causal. Evidence of cryptic splicing resulting in novel exon transcription for FAM134B was identified by RNAseq experiments. This investigation demonstrates the identification of a novel sensory neuropathy associated mutation, by mapping using a minimal set of cases and subsequent genome sequencing. Through mutation screening, it should be possible to reduce the frequency of or completely eliminate this debilitating condition from the Border Collie breed population.

Two mixed breed dogs with sensory neuropathy are homozygous for an inversion disruptingFAM134Bpreviously identified in Border Collies

“…Because of clinical and histopathological similarities with previously reported Border Collie sensory neuropathy and despite the fact that the dog did not resemble a Border Collie (Figure ), it was decided to screen for the recently reported mutation in the FAM134B gene and the dog was found to be homozygous.…”

“…Serology testing for T. gondii and N. caninum was negative. Again, because of the clinical similarities with previously reported Border Collie sensory neuropathy, the dog was screened for the recently reported mutation in the FAM134B gene and found to be homozygous. Phenotypically, the dog did not resemble a Border Collie (Figure ).…”

“…Herein we describe 2 cases of sensory neuropathy caused by an inversion disrupting FAM134B in a dog other than a pure‐breed Border Collie. Sensory neuropathy in the Border Collie is an autosomal recessive disease characterized by chronic and progressive proprioceptive ataxia, proprioceptive deficits, loss of nociception, self‐mutilation, and in some cases, autonomic signs such as urinary incontinence . Recently, a genetic mutation was found affecting the FAM134B gene in Border Collies with clinical signs compatible with sensory neuropathy .…”

“…The FAM134B gene encodes a cis‐Golgi protein found in sensory and autonomic neurons. Although not completely understood, this defect induces apoptosis in neurons of the dorsal root ganglia …”

Peer Review #2 of "Charcot-Marie-Tooth type 4B2 demyelinating neuropathy in miniature Schnauzer dogs caused by a novel splicing SBF2 (MTMR13) genetic variant: a new spontaneous clinical model (v0.1)"

“…Older neuropathies, such as the well-known inherited sensory and autonomic in the Border Collie first described in 1987 [21], have also benefited from genetic advances. In 2016 one causal genetic variant of FAM134B, which encodes a cis-Golgi protein found in sensory and autonomic ganglion neurons, has been discovered [22] and two-years later, this mutation was also described in two mixed breed dogs [23]. In four other breeds, the German short-haired Pointer, the English Pointer, the English Springer Spaniel and the French Spaniel, some known since 1964, a similar inherited sensory and autonomic exist and found to be linked to a genetic variation of the long-non-coding RNA located upstream of the Glial cell-Derived Neurotrophic Factor gene, coding for a neurotrophic factor involved in neuronal development and adult neuronal survival [24].…”