Hereditary sensory and autonomic neuropathy in a family of mixed breed dogs associated with a novel RETREG1 variant

Abstract

Background Hereditary sensory and autonomic neuropathies (HSANs) are a group of genetic disorders affecting the peripheral nervous system. Two different associated variants have been identified in dogs: 1 in Border Collies and 1 in Spaniels and Pointers. Objectives Clinically and genetically characterize HSAN in a family of mixed breed dogs. Animals Five 7‐month‐old mixed breed dogs from 2 related litters were presented for evaluation of a 2‐month history of acral mutilation and progressive pelvic limb gait abnormalities. Methods Complete physical, neurological, electrodiagnostic, and histopathological evaluations were performed. Whole genome sequencing of 2 affected dogs (1 from each litter) was used to identify variants that were homozygous or heterozygous in both cases, but wild type in 217 control genomes of 100 breeds. Immunohistochemistry was used to assess protein expression. Results Complete physical, neurological, electrodiagnostic, and histopathological evaluations confirmed a disorder affecting sensory and autonomic nerves. Whole genome sequencing identified a missense variant in the RETREG1 (reticulophagy regulator 1) gene (c.656C > T, p.P219L). All affected dogs were homozygous for the variant, which was not detected in 1193 dogs from different breeds. Immunohistochemistry showed no expression of RETREG1 in the cerebellum of affected dogs. One of the affected dogs lived for 5 years and showed gradual progression of the clinical signs. Conclusions and Clinical Importance We confirmed the diagnosis of HSAN in a family of mixed breed dogs and identified a novel and possibly pathogenic RETREG1 variant. Affected dogs experienced gradual deterioration over several years.

SCN9A variant in a family of mixed breed dogs with congenital insensitivity to pain

“…When compared with previous reports of HSAN and CIP in dogs, the dogs of our study share more similarities with the Miniature Pinscher, 14 Pointer, 4,6‐8 Spaniel, 4,5 and Fox Terrier, 18 that presented with loss of pain sensation, but no proprioceptive deficits or autonomic signs. In contrast, the HSAN reported in the long‐haired Dachshund, 15,16 Jack Russell Terrier, 17 Border Collie, 9‐13 and a family of mixed breed dogs 19 was associated with other neurological deficits including proprioceptive deficits and signs of autonomic dysfunction. An important difference in the dogs of our report is that automutilation was not a feature, but severe injuries were caused by external sources.…”

“…The first is an inversion disrupting RETREG1 ( reticulophagy regulator 1 ) in Border Collies and Border Collie crosses with HSAN (OMIA 002032‐9615) 9,13 . The second is a missense variant in the same gene in a family of mixed breed dogs with HSAN (OMIA 002032‐9615) 19 . The third variant is a regulatory single base substitution in a lincRNA upstream of the GDNF ( glial cell‐derived neurotrophic factor ) gene encoding glial cell‐derived neurotrophic factor in Pointers, English Springer Spaniels and French Spaniels with acral mutilation syndrome (OMIA 001514‐9615) 4 …”

“…2,3 In humans, seven forms of CIP and eight forms of HSAN have been described based on phenotype, and genetic variants in at least 26 genes have been reported. 2,3 Congenital insensitivity to pain and HSANs have been described previously in some dog breeds including French Spaniel, 4,5 English Springer Spaniel, 4,5 Pointer, 4,[6][7][8] Border Collie, [9][10][11][12] Border Collie cross, 13 Miniature Pincher, 14 Long-haired Dachshund, 15,16 Jack Russell Terrier, 17 Fox Terrier, 18 and a family of mixed breed dogs, 19 but only three causal genetic variants have been identified to date. The first is an inversion disrupting RETREG1 (reticulophagy regulator 1) in Border Collies and Border Collie crosses with HSAN (OMIA 002032-9615).…”

The number of mitochondrial DNA mutations as a genetic feature for hair cycle arrest (alopecia X) in Pomeranian dogs

“…12 Whole-genome sequencing was done for a variety of hereditary diseases in dogs to find novel genetic variants. 13,14 The aim of this study was to identify HCA-related genes in Pomeranian dogs using WGS. Identification of candidate genes may eventually contribute to early diagnosis, appropriate breeding and development of new therapies.…”

“…By contrast, whole‐genome sequencing (WGS) can comprehensively analyse the entire genome, allowing the screening of multiple untargeted genetic variants and increasing the likelihood of identifying unknown genetic mutations 12 . Whole‐genome sequencing was done for a variety of hereditary diseases in dogs to find novel genetic variants 13,14 …”