In other species: dog , domestic cat , taurine cattle , goat , sheep , Magellanic penguin

Categories: Nervous system phene

Links to possible relevant human trait(s) and/or gene(s) in OMIM: 600224 (trait)

Mendelian trait/disorder: yes

Mode of inheritance: Autosomal recessive

Disease-related: yes

Key variant known: yes

Year key variant first reported: 2011

Cross-species summary: Also known as neonatal cerebellar cortical degeneration (NCCD)

Species-specific symbol: CA

History: Before 1966, equine cerebellar hypoplasia and degeneration was believed to only occur in pure-bred Arabians. Then, Fraser (1966) described the first incidence of the disease in a half-Arab female foal in the United Kingdom. The next year, Sponseller (1967) reported an incidence of 17 males out of 21 cases in the United States (cited by Baird and Mackenzie, 1974). The first researched cases of cerebellar hypoplasia and degeneration occurred in 2 foals, born in 1969 and 1970 respectively, known as Case 1 and Case 2, which were offspring of matings between a Thoroughbred/Pony-crossed mare and 2 Arabian stallions (Baird and Mackenzie, 1974). {slightly modified from text provided by Meredith O’Connell, working under the supervision of Professor E. Bailey}

Inheritance: “Results of the complex segregation analysis were consistent with a single Mendelian autosomal recessive mode of inheritance” (Brault et al., AJVR, 2011). {text provided by Meredith O’Connell, working under the supervision of Professor E. Bailey}

Mapping: Brault et al. (Genomics, 2011) mapped CA to the p-arm of ECA2 by performing a whole genome scan on four paternal families of Arabian horses segregating for CA. “Further marker development in the identified region, as well as homozygosity analysis in affected foals, refined the CA region to approximately 142 kb” (Brault et al., Genomics, 2011). {slightly modified from text provided by Meredith O’Connell, working under the supervision of Professor E. Bailey}

Molecular basis: “The CA region contains four annotated genes, including MUTYH and TOE1, both of which are potential candidate genes. . . . One SNP identified [ECA2:13074277G>A as reported in this paper] was found to be exclusive to the Arabian breed and to be completely concordant with the CA trait, making it an excellent candidate for the CA mutation. This SNP is located in exon 4 of TOE1 but results in a relatively benign amino acid substitution . . . . However, it is also located approximately 1200 base pairs 5− of the start site of MUTYH, which is transcribed from the opposite strand, and is immediately adjacent to a possible binding site for the transcription factor GATA2. The results of a qPCR analysis on RNA extracted from the cerebella of affected and unaffected horses suggest that MUTYH expression is reduced in affected horses. The putative CA SNP may therefore have a regulatory effect on MUTYH by affecting the binding affinity of GATA2” (Brault et al., Genomics, 2011). In a subsequent study, Scott et al. (2017) reported that differential expression of TOE1 and MUTYH was not observed, but both genes remain candidates for CA: “Three pipelines for differential gene expression (DE) analysis were used (Tophat2/Cuffdiff2, Kallisto/EdgeR, and Kallisto/Sleuth) with 151 significant DE genes identified by all three pipelines in CA-affected horses. TOE1 . . . and MUTYH . . . were not differentially expressed. Among the major pathways that were differentially expressed, genes associated with calcium homeostasis and specifically expressed in Purkinje neurons, CALB1 . . . and CA8 . . . , were significantly down-regulated, confirming loss of Purkinje neurons. There was also a significant up-regulation of markers for microglial phagocytosis, TYROBP . . . and TREM2 . . . . These findings reaffirm a loss of Purkinje neurons in CA-affected horses along with a potential secondary loss of granular neurons and activation of microglial cells.” {slightly modified from text provided by Meredith O’Connell, working under the supervision of Professor E. Bailey}

Clinical features: Brault et al. 2011 (Genomics): "Cerebellar abiotrophy (CA) is a neurological condition, characterized by post-natal degeneration of Purkinje cells of the cerebellum . . . Symptoms of CA in horses generally appear between six weeks and four months of age and include intention head tremors, ataxia, exaggerated or paddling action of the forelegs, a wide-based stance and a lack of menace response . . . . Affected horses may startle easily and fall, and are often unable to rise from a reclining position”. {slightly modified from text provided by Meredith O’Connell, working under the supervision of Professor E. Bailey}

Prevalence: Other than the strong prevalence known in Arabians, “At least one CA carrier was identified in 3 breeds and the frequency of the CA allele calculated: Bashkir Curly Horses (2.8%), Trakehners (0.68%) and Welsh ponies (0.33%). Based on pedigree and haplotype analysis, CA was introduced into these breeds by Arabian ancestry. The Trakehner and Welsh pony carriers were at least half-Arabian, while the Bashkir Curly horses appeared to have had the CA allele introduced by a single Arabian stallion used for developing the breed in the 1960s” (Brault, et al., EVJ, 2011). {text provided by Meredith O’Connell, working under the supervision of Professor E. Bailey}

Breeds: Arab (Horse) (VBO_0000905), Bashkir Curly (Horse) (VBO_0000913), Icelandic Horse (Horse) (VBO_0000991), Trakehner (Horse) (VBO_0001087), Welsh Pony (Horse) (VBO_0001091).
Breeds in which the phene has been documented. (If a likely causal variant has been documented for the phene, see the variant table breeds in which the variant has been reported).

Associated genes: