Searching the genetic bases of neuropathies in several dog breeds as models for human neuropathies: identification of a RETREG1 variant in purebred German spitz

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Authors Pascale Quignon (1), Anna Letko (1), Jocelyn Plassais (1), Maeva Quilléré (1), Richard Guyon (1), Catherine André (1)
Affiliations 1. IGDR, Institut de Génétique et Développement de Rennes Univ Rennes – CNRS UMR6290, Medical Faculty, 35000 Rennes, France
Presentation Type Talk


Canine acral mutilation syndrome (AMS) is a neurological disease severely impacting the quality of life and documented for decades as part of inherited sensory neuropathy in various breeds. Nevertheless, causal variants in only two genes were identified to date, suggesting larger genetic heterogeneity exists in the dog population, with several breeds being specifically affected. In humans, the equivalent disease is hereditary sensory autonomic neuropathy (HSAN), characterized by insensitivity to pain, sometimes also combined with self-mutilation. Sixteen loci have been
associated with HSAN but do not explain the disease origin of all patients.

Our aim is to explain the genetic etiology of early-onset AMS in several dog breeds, including German spitz, Pinschers and Fox terriers. For each breed, affected dogs and their family have been sampled and 3 to 4 dogs per family have been sequenced, through Whole Genome Sequence.

For German spitz dogs, affected dogs showed loss of pain sensation in the distal extremities, which lead to intense licking, biting, and self-mutilation of digits, claws, and paw pads, resulting in skin lesions, progressing to the point of auto-amputation of distal phalanges and claws. DNA was isolated from blood samples of a Spitz case, its parents, and three unaffected German spitz. Whole-genome sequencing (WGS) of the case, its dam, and two controls was carried out to search for causal genetic variants using the reference genome assembly UU_Cfam_GSD_1.0. Single nucleotide variants and small indels private to the single case were called from the WGS data. The list of variants was filtered based on autosomal recessive inheritance and variants were further prioritized by predicted impact on the encoded protein and allele frequency in a cohort of 961 publically available canine WGS. A single candidate causal variant on chromosome 4 in the RETREG1 gene (c.656C>T, p.Pro219Leu) was discovered. Genotyping showed the variant segregated perfectly in the German spitz family and was absent in other unrelated spitz dogs.

The missense variant was previously recognized as deleterious in one mixed-breed dog family with similar clinical signs. Disruption of RETREG1 inhibits endoplasmic reticulum turnover and leads to neuron degeneration. Different RETREG1 variants are already identified to cause HSAN in humans. Our findings provide evidence that this variant underlies the recessive form of AMS in German spitz, and support the use of veterinary molecular genetics for early diagnosis and for prediction and selection for breeders of such dramatic genetic diseases. In a comparative pathology and genetic approach, it provides either new candidates, or natural models of the corresponding Human HSAN terrible diseases.