Missense Mutation in CAPN1 Is Associated with Spinocerebellar Ataxia in the Parson Russell Terrier Dog Breed

Abstract

Spinocerebellar ataxia (SCA) in the Parson Russell Terrier (PRT) dog breed is a disease of progressive incoordination of gait and loss of balance. Clinical signs usually become notable between 6 and 12 months of age with affected dogs presenting with symmetric spinocerebellar ataxia particularly evident in the pelvic limbs. The degree of truncal ataxia, pelvic limb hypermetria and impaired balance is progressive, particularly during the initial months of disease. A certain degree of stabilisation as well as intermittent worsening may occur. At the later stages of the disease ambulation often becomes difficult, with owners often electing to euthanise affected dogs on welfare grounds. Using a GWAS approach and target-enriched massively-parallel sequencing, a strongly associated non-synonymous SNP in the CAPN1 gene, encoding the calcium dependent cysteine protease calpain1 (mu-calpain), was identified. The SNP is a missense mutation causing a cysteine to tyrosine substitution at residue 115 of the CAPN1 protein. Cysteine 115 is a highly conserved residue and forms a key part of a catalytic triad of amino acids that are crucial to the enzymatic activity of cysteine proteases. The CAPN1 gene shows high levels of expression in the brain and nervous system and roles for the protein in both neuronal necrosis and maintenance have been suggested. Given the functional implications and high level of conservation observed across species, the CAPN1 variant represents a provocative candidate for the cause of SCA in the PRT and a novel potential cause of ataxia in humans.

The novel homozygous KCNJ10 c.986T>C (p.(Leu329Pro)) variant is pathogenic for the SeSAME/EAST homologue in Malinois dogs

“…6,8 In knockdown mice, hypomyelination in the spinal cord with severe spongiform vacuolation, axonal swelling and degeneration is also described. 46 To the author's knowledge, there are currently no pathological reports available of humans with SeSAME/EAST syndrome.…”

“…Until now, only the KCNJ10 c.627C4G (p.(Ile209Met)) variant has been reported to be associated with spinocerebellar ataxia and myokymia, seizures or both (SAMS) in certain Terrier breeds. 6,7 In addition, Forman et al 8 reported that the CAPN1 c.344G4A (p.(Cys115Tyr)) variant is strongly associated with late-onset ataxia in Parson Russell Terriers, suggesting that CAPN1 may represent a novel candidate gene for ataxia in humans. According to OMIA there are no spontaneous disease causing variants in KCNJ10 described in other species.…”

Canine Hereditary Ataxia

“…Spinocerebellar degeneration has been reported in Brittany Spaniels, 39 Jack Russell Terriers, Parson Russell Terriers, [6][7][8][9] and Smooth-haired Fox Terriers (also known as Russell Terrier Group) (see Table 1). 40,41 Brittany Spaniels suffer from late-onset (5-10.7 years) spinocerebellar degeneration.…”

“…This disease has been associated with a missense mutation in CAPN1. 9 The CAPN1 gene encodes an intracellular calcium-dependent cysteine protease called calpain 1. Although the exact function of calpain 1 is unknown, it is proposed to play a role in neuronal maintenance and remodeling; this represents a third disorder in which potential defects in disposal of proteins results in neuronal degeneration.…”

“…It is noticeable when reading the veterinary literature that many different terms are used to describe these diseases, and in some instances (eg, the Russell Terrier group) at least 2 clinically similar, but genetically distinct disorders occur, leading to an extremely confusing clinical picture. [6][7][8][9] In this article, the authors attempt to place the most well-described diseases into consistent categories to limit confusion. The categories of diseases included under the term "hereditary ataxia" in this article are as follows:…”