RNF170 frameshift deletion in Miniature American Shepherd dogs with neuroaxonal dystrophy provides a naturally occurring model for human RNF170 phenotypic spectrum

Author:

Cook Shawna R.1,Schwarz Cleo2,Guevar Julien3,Assenmacher Charles-Antoine4,Sheehy Maeve1,Fanzone Nathan4,Church Molly E.4,Murgiano Leonardo4,Casal Margret L.4,Jagannathan Vidhya2,Gutierrez-Quintana Rodrigo5,Lowrie Mark6,Steffen Frank7,Leeb Tosso2,Ekenstedt Kari J.1

Affiliation:

1. Purdue University

2. University of Bern

3. AniCura Thun

4. University of Pennsylvania

5. University of Glasgow

6. Movement Referrals: Independent Veterinary Specialists

7. University of Zurich

Abstract

Abstract Neuroaxonal dystrophy (NAD) is a group of inherited neurodegenerative disorders characterized primarily by the presence of spheroids (swollen axons) throughout the central nervous system. In humans, NAD is heterogeneous, both clinically and genetically. NAD has also been described to naturally occur in large animal models, such as dogs. A newly recognized disorder in Miniature American Shepherd dogs (MAS), consisting of a slowly progressive neurodegenerative syndrome, was diagnosed as NAD via histopathology. Affected dogs were typically young adults and displayed an abnormal gait characterized by pelvic limb weakness and ataxia. A combined GWAS and autozygosity mapping approach, together with whole-genome sequencing, identified the underlying genetic cause as a 1-bp deletion in RNF170 (ring finger protein 170), which perfectly segregates in an autosomal recessive pattern. This deletion is predicted to create a frameshift (XM_038559916.1:c.367delG) and early truncation of the RNF170 protein (XP_038415844.1:(p.Ala123Glnfs*11). A significant LOD score of 9.70 in an extended pedigree confirms the linkage of the deletion variant with the canine phenotype. Several RNF170 variants have been identified in human patients with analogous clinical syndromes, indicating that this novel MAS NAD serves as an excellent large animal model for equivalent human diseases, particularly since affected dogs demonstrate a relatively long lifespan, which represents an opportunity for therapeutic trials. The age of this canine RNF170 variant is estimated at approximately 30 years, before the reproductive isolation of the MAS breed. This carries implications for the standard Australian Shepherd, the breed from which MAS were developed.

Publisher

Research Square Platform LLC

Reference47 articles.

1. A PNPLA8 frameshift variant in Australian shepherd dogs with hereditary ataxia;Abitbol M;Anim Genet,2022

2. Neuroaxonal dystrophy in a two-year-old quarter horse filly;Adams AP;Can Vet J,1996

3. Blackstone C (2018) Hereditary spastic paraplegia, 1st edn. Elsevier B.V.

4. Spontaneous Murine Neuroaxonal Dystrophy: a Model of Infantile Neuroaxonal Dystrophy;Bouley DM;J Comp Pathol,2006

5. Neuroaxonal Dystrophy in a Group of Related Cats;Carmichael KP;J Vet Diagnostic Investig,1993

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