Identification of a novel <i>CLPX</i> variant in a mixed breed dog with anemia and spinocerebellar ataxia

bioRxiv (Cold Spring Harbor Laboratory) · 2025-09-18

Abstract Spinocerebellar ataxia (SCA) or hereditary ataxia is a progressive neurodegenerative disorder primarily manifesting as cerebellar or spinocerebellar dysfunction, resulting in the loss of motor control and voluntary muscle coordination. SCAs are typically inherited conditions, with causative genetic variants identified in multiple genes in people and across various dog breeds. Recently, an atypical case of SCA was documented in a mixed breed dog. In addition to the classic clinical signs and spinocerebellar lesions of SCA, the dog had retinal and optic nerve degeneration and severe, non-regenerative anemia. Whole-genome sequence (WGS) of the affected dog did not reveal any previously identified canine SCA-associated variants. Subsequent variant filtering against a control cohort of over 700 unaffected dog genomes identified a homozygous 4-base-pair frameshift deletion in caseinolytic mitochondrial matrix peptidase chaperone subunit X ( CLPX ) [XM_038580726.1:c.1723_1726del]. CLPX encodes a subunit of the ATP-dependent ClpXP protease, a molecular chaperone involved in mitochondrial protein degradation. The variant is predicted to cause a frameshift and a premature stop codon within 17 amino acids, truncating approximately 6.64% of the protein. Our study is the first to explore the association of CLPX variants with SCA in any species. Given the high evolutionary conservation of CLPX , this report of a CLPX variant associated with SCA in a dog may have relevance for understanding CLPX -related neurodegeneration and/or anemia in other species. Author Summary A young mixed-breed dog developed a gait abnormality that progressively worsened, together with vision loss, and severe anemia. Despite treatment, the dog’s condition deteriorated, and he was humanely euthanized. An autopsy revealed extensive abnormalities in the brain, spinal cord, eyes, and bone marrow. These histologic findings supported a diagnosis of spinocerebellar ataxia (SCA), also known as hereditary ataxia, which is a genetic neurological disorder that results in impaired movement and diminished coordination. Genetic analysis identified a previously unreported mutation in the CLPX gene. CLPX plays a key role in mitochondrial protein quality control by helping break down damaged or misfolded proteins within mitochondria—cell structures critical for energy production that are particularly crucial in high-demand tissues like the brain. This mutation likely disrupted normal CLPX protein function, leading to both nerve damage and impaired blood cell production. While related genes are known to cause similar conditions in humans, this is the first time a naturally occurring CLPX variant has been identified in an SCA case in any species. Because CLPX is highly conserved between dogs and humans, this finding may offer valuable insights into rare inherited neurological diseases in people.

<scp> <i>ABCA12</i> </scp> Frameshift Deletion in Domestic Cats With Ichthyosis Fetalis

Veterinary Dermatology · 2025-12-15

BACKGROUND: Ichthyosis fetalis (IF), also known as harlequin ichthyosis, is a rare and often fatal autosomal recessive congenital skin disorder. It is characterized by thickened, hard skin plaques and deep skin fissures that limit mobility and cause malformations of the eyes, lips and ears. Affected individuals are highly susceptible to life-threatening infections due to the disruption of the skin's protective barrier. To date, IF and its genetic basis have not been described in domestic cats. OBJECTIVES: To characterize the gross clinical, histopathological and genetic features of IF in two stray, random-bred domestic short-hair (DSH) littermates. ANIMALS: Two deceased female neonatal DSH kittens, both exhibiting sparse hair and deep fissures exposing the underlying dermis. One unrelated neonatal kitten with normal skin and hair was included as a control for comparison, along with 140 feline population samples from unrelated domestic cats of various breeds. MATERIALS AND METHODS: Gross clinical examination, histopathological analysis, whole-genome sequencing and population genotyping were performed. RESULTS: Gross clinical and histopathological evaluations confirmed a diagnosis of IF in both affected kittens. Genetic analysis identified a homozygous one base pair deletion in ABCA12, resulting in a frameshift and predicted loss of function of the encoded protein. Genotyping of 140 unrelated cats revealed that all were homozygous for the wild-type allele. CONCLUSIONS AND CLINICAL RELEVANCE: Variants in ABCA12 have been implicated previously in IF in humans, cattle and mice. This study provides the first description of IF in domestic cats and identifies a pathogenic ABCA12 frameshift variant as the likely genetic cause.

Identification of a novel RBCK1 splice site donor variant in Basset Hounds with glycogen storage disease myopathy

Molecular Genetics and Metabolism · 2025-09-01 · 1 citations

Identification of a Novel CLPX Variant in a Mixed-Breed Dog with Anemia and Spinocerebellar Ataxia

Genes · 2025-11-10

Background/Objectives: Spinocerebellar ataxia (SCA), or hereditary ataxia, is a progressive neurodegenerative disorder primarily affecting motor control and voluntary muscle coordination due to cerebellar or spinocerebellar dysfunction. While numerous genetic variants have been linked to SCA in both humans and dogs, some cases remain genetically unexplained. This study aimed to describe the clinical and pathological phenotype, and to identify the genetic basis, of an atypical form of SCA observed in a mixed-breed dog presenting with additional clinical signs beyond classic SCA. Methods: Clinical and postmortem examinations were performed to document neurological and systemic pathology. Whole-genome sequencing (WGS) was conducted on the affected dog, and variant filtering was carried out using a control cohort of over 700 unaffected dog genomes to identify candidate variants. Results: In addition to classical SCA features, the affected dog exhibited retinal and optic nerve degeneration and severe, non-regenerative anemia. WGS did not reveal any known SCA-associated variants. Variant filtering identified a novel homozygous 4-base-pair frameshift deletion in CLPX (caseinolytic mitochondrial matrix peptidase chaperone subunit X) [XM_038580726.1:c.1723_1726del; chr30:g.29943285_29943288del]. This variant is predicted to cause a frameshift and premature stop codon within 17 amino acids, truncating approximately 6.64% of the protein. Conclusions: This is the first report associating a CLPX variant with SCA in any species. Given the gene’s high evolutionary conservation and known role in mitochondrial protein homeostasis, this finding may have implications for understanding CLPX-related neurodegeneration and anemia in both veterinary and human medicine.

Moving from information and collaboration to action: report from the 5th International Dog Health Workshop in Helsinki, June 2024

Companion Animal Health and Genetics · 2025-04-09

Abstract Background The International Partnership for Dogs, together with a rotating national host organisation, holds approximately biennial meetings called the International Dog Health Workshop (IDHW). These workshops bring together a broad range of stakeholders in dog health and welfare, including scientists and veterinary practitioners, to improve the international sharing of information and resources, to provide a forum for ongoing collaboration, and to identify and agree on specific needs and actions to improve canine health and welfare. Workshop presentation 5th International Dog Health Workshop was hosted by the Finnish Kennel Club in Helsinki, Finland, in June 2024. The workshop was structured around four key issues facing those working to improve dog health: ‘Supply and Demand’, ‘Breeding for Health and Well-Being’, ‘Big Data’, and ‘Does the Colour Matter? Defining Breed vs. Variety’. The workshop provided an opportunity for participants to meet face-to-face after a five-year hiatus due to COVID-19, on the 10 th anniversary of the International Partnership for Dogs. Among the 106 decision-makers from 16 countries who attended the workshop, there was broad agreement on several issues during the discussions, such as following the scientific evidence on canine genetics and health, moving away from extreme conformation, and using all available tools, including crossbreeding, to maintain and increase genetic variation within dog breeds. It was agreed that these principles should become priorities for welfare-minded organisations at the national and international levels. Better education of puppy buyers, breeders, show judges, and other relevant parties was recurringly identified as a priority across all four themes of the workshop. Conclusions In summary, key agreements from the 5th IDHW were that organisations must comply fully with relevant national animal welfare legislation, that organisations must work to eliminate extreme conformations from all dogs and to improve and maintain genetic diversity within subpopulations of dogs, and that organisations should recognise and support crossbreeding as an accepted and valuable tool for modern dog breeding.

Heritability and genome-wide association study of vaccine-induced immune response in Beagles: A pilot study

Vaccine · 2024-04-01 · 4 citations

Both genetic and non-genetic factors contribute to individual variation in the immune response to vaccination. Understanding how genetic background influences variation in both magnitude and persistence of vaccine-induced immunity is vital for improving vaccine development and identifying possible causes of vaccine failure. Dogs provide a relevant biomedical model for investigating mammalian vaccine genetics; canine breed structure and long linkage disequilibrium simplify genetic studies in this species compared to humans. The objective of this study was to estimate the heritability of the antibody response to vaccination against viral and bacterial pathogens, and to identify genes driving variation of the immune response to vaccination in Beagles. Sixty puppies were immunized following a standard vaccination schedule with an attenuated combination vaccine containing antigens for canine adenovirus type 2, canine distemper virus, canine parainfluenza virus, canine parvovirus, and four strains of Leptospira bacteria. Serum antibody measurements for each viral and bacterial component were measured at multiple time points. Heritability estimations and GWAS were conducted using SNP genotypes at 279,902 markers together with serum antibody titer phenotypes. The heritability estimates were: (1) to Leptospira antigens, ranging from 0.178 to 0.628; and (2) to viral antigens, ranging from 0.199 to 0.588. There was not a significant difference between overall heritability of vaccine-induced immune response to Leptospira antigens compared to viral antigens. Genetic architecture indicates that SNPs of low to high effect contribute to immune response to vaccination. GWAS identified two genetic markers associated with vaccine-induced immune response phenotypes. Collectively, these findings indicate that genetic regulation of the immune response to vaccination is antigen-specific and influenced by multiple genes of small effect.

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

Research Square · 2024-02-01

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.

Mapping the locus for ocular melanosis in Cairn Terriers

Veterinary Ophthalmology · 2024-10-24

OBJECTIVE: To map the disease locus for familial ocular melanosis (OM) in the Cairn Terrier. ANIMALS STUDIED: Cairn Terriers with OM and normal control dogs. PROCEDURE: A genome-wide association study (GWAS) was performed using 63 OM-affected and 31 control Cairn Terriers, followed by haplotype analysis. A significantly associated single-nucleotide polymorphism was genotyped in a larger group of OM-affected and control Cairn Terriers. The coding and splice-site regions of genes mapping within the confidence interval were sequenced. RESULTS: A ~9.2 Mb region of chromosome 11 was significantly associated with OM. Haplotype analysis narrowed the region to 1.49 Mb. Genotyping of a SNP within the region showed 86% of OM-affected dogs were homozygous or heterozygous for the risk allele, whereas 78% of unaffected dogs were homozygous for the nonrisk allele. Sequencing of the coding regions and splice sites of four genes (c9orf72, IFNK, the 5' end of MOB3B, and the 3' end of LINGO2) and of a microRNA (MIR876) did not detect any genetic variants unique to OM-affected dogs. CONCLUSION: OM in Cairn Terriers maps to a 1.49 Mb region of chromosome 11. This accounts for 86% of OM cases in our DNA bank. A second locus may account for the OM phenotype in the remaining 14% of cases. Sequencing of coding regions and splice sites of positional candidate genes and a microRNA did not reveal any genetic variants unique to affected dogs. Further studies are required to elucidate the DNA variant causal for OM in Cairn Terriers and to understand the disease mechanism.

Heritability and Genome-Wide Association Study of Dog Behavioral Phenotypes in a Commercial Breeding Cohort

Genes · 2024-12-17 · 4 citations

Background: Canine behavior plays an important role in the success of the human–dog relationship and the dog’s overall welfare, making selection for behavior a vital part of any breeding program. While behaviors are complex traits determined by gene × environment interactions, genetic selection for desirable behavioral phenotypes remains possible. Methods: No genomic association studies of dog behavior to date have been reported on a commercial breeding (CB) cohort; therefore, we utilized dogs from these facilities (n = 615 dogs). Behavioral testing followed previously validated protocols, resulting in three phenotypes/variables [social fear (SF), non-social fear (NSF), and startle response (SR)]. Dogs were genotyped on the 710 K Affymetrix Axiom CanineHD SNP array. Results: Inbreeding coefficients indicated that dogs from CB facilities are statistically less inbred than dogs originating from other breeding sources. Heritability estimates for behavioral phenotypes ranged from 0.042 ± 0.045 to 0.354 ± 0.111. A genome-wide association analysis identified genetic loci associated with SF, NSF, and SR; genes near many of these loci have been previously associated with behavioral phenotypes in other populations of dogs. Finally, genetic risk scores demonstrated differences between dogs that were more or less fearful in response to test stimuli, suggesting that these behaviors could be subjected to genetic improvement. Conclusions: This study confirms several canine genetic behavioral loci identified in previous studies. It also demonstrates that inbreeding coefficients of dogs in CB facilities are typically lower than those in dogs originating from other breeding sources. SF and NSF were more heritable than SR. Risk allele and weighted risk scores suggest that fearful behaviors could be subjected to genetic improvement.

Canine <scp><i>RNF170</i></scp> Single Base Deletion in a Naturally Occurring Model for Human Neuroaxonal Dystrophy

Movement Disorders · 2024-08-23 · 3 citations

BACKGROUND: 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. OBJECTIVES: To describe the clinical and pathological phenotype together with the identification of the underlying genetic cause. METHODS: Clinical and postmortem evaluations, together with a genome-wide association study and autozygosity mapping approach, followed by whole-genome sequencing. RESULTS: Affected dogs were typically young adults and displayed an abnormal gait characterized by pelvic limb weakness and ataxia. The underlying genetic cause was identified as a 1-bp (base pair) deletion in RNF170 encoding 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)). The age of this canine RNF170 variant was estimated at ~30 years, before the reproductive isolation of the MAS breed. CONCLUSIONS: RNF170 variants were previously identified in human patients with autosomal recessive spastic paraplegia-85 (SPG85); this clinical phenotype shows similarities to the dogs described herein. We therefore propose that this novel MAS NAD could serve 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. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.