OMIA 000175-9796 : Cerebellar abiotrophy in Equus caballus

In other species: dog , sheep , domestic cat , cattle , goat

Possibly relevant human trait(s) and/or gene(s) (MIM number): 600224

Mendelian trait/disorder: yes

Mode of inheritance: Autosomal Recessive

Considered a defect: 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: Arabian, Bashkir Curly Horse, Trakehner, Welsh Pony.

Associated genes:

Symbol Description Species Chr Location OMIA gene details page Other Links
MUTYH mutY DNA glycosylase Equus caballus 2 NC_009145.3 (12981762..13140182) MUTYH Homologene, Ensembl, NCBI gene
TOE1 target of EGR1, member 1 (nuclear) Equus caballus 2 NC_009145.3 (13123771..13120229) TOE1 Homologene, Ensembl, NCBI gene

Variants

By default, variants are sorted chronologically by year of publication, to provide a historical perspective. Readers can re-sort on any column by clicking on the column header. Click it again to sort in a descending order. To create a multiple-field sort, hold down Shift while clicking on the second, third etc relevant column headers.

WARNING! Inclusion of a variant in this table does not automatically mean that it should be used for DNA testing. Anyone contemplating the use of any of these variants for DNA testing should examine critically the relevant evidence (especially in breeds other than the breed in which the variant was first described). If it is decided to proceed, the location and orientation of the variant sequence should be checked very carefully.

Breed(s) Variant Phenotype Gene Allele Type of Variant Reference Sequence Chr. g. or m. c. or n. p. Verbal Description EVA ID Year Published PubMed ID(s) Acknowledgements
Arabian Bashkir Curly Horse Trakehner Welsh Pony Cerebellar abiotrophy MUTYH not known EquCab 3.0 2 g.13122415G>A A SNP "located in exon 4 of TOE1 and approximately 1200 base pairs upstream of MUTYH, adjacent to a possible binding site for the transcription factor GATA2" (Brault et al., 2011). EquCab3.1 coordinate provided by Meredith O’Connell, working under the supervision of Professor E. Bailey. 2011 21126570

References


Note: the references are listed in reverse chronological order (from the most recent year to the earliest year), and alphabetically by first author within a year.
2017 Scott, E.Y., Penedo, M.C., Murray, J.D., Finno, C.J. :
Defining Trends in Global Gene Expression in Arabian Horses with Cerebellar Abiotrophy. Cerebellum 16:462-472, 2017. Pubmed reference: 27709457. DOI: 10.1007/s12311-016-0823-8.
2016 Sadaba, S.A., Madariaga, G.J., Botto, C.M., Carino, M.H., Zappa, M.E., García, P.P., Olguín, S.A., Massone, A., Díaz, S. :
First report of cerebellar abiotrophy in an Arabian foal from Argentina. Open Vet J 6:259-262, 2016. Pubmed reference: 28116251. DOI: 10.4314/ovj.v6i3.17.
2014 Tarr, C.J., Thompson, P.N., Guthrie, A.J., Harper, C.K. :
The carrier prevalence of severe combined immunodeficiency, lavender foal syndrome and cerebellar abiotrophy in Arabian horses in South Africa. Equine Vet J 46:512-4, 2014. Pubmed reference: 24033554. DOI: 10.1111/evj.12177.
2013 Cavalleri, J.M., Metzger, J., Hellige, M., Lampe, V., Stuckenschneider, K., Tipold, A., Beineke, A., Becker, K., Distl, O., Feige, K. :
Morphometric magnetic resonance imaging and genetic testing in cerebellar abiotrophy in Arabian horses. BMC Vet Res 9:105, 2013. Pubmed reference: 23702154. DOI: 10.1186/1746-6148-9-105.
2011 Brault, L.S., Penedo, M.C. :
The frequency of the equine cerebellar abiotrophy mutation in non-Arabian horse breeds. Equine Vet J 43:727-31, 2011. Pubmed reference: 21496100. DOI: 10.1111/j.2042-3306.2010.00349.x.
Brault, LS., Cooper, CA., Famula, TR., Murray, JD., Penedo, MC. :
Mapping of equine cerebellar abiotrophy to ECA2 and identification of a potential causative mutation affecting expression of MUTYH. Genomics 97:121-129, 2011. Pubmed reference: 21126570. DOI: 10.1016/j.ygeno.2010.11.006.
Brault, LS., Famula, TR., Penedo, MC. :
Inheritance of cerebellar abiotrophy in Arabians. Am J Vet Res 72:940-4, 2011. Pubmed reference: 21728855. DOI: 10.2460/ajvr.72.7.940.
2006 Blanco, A., Moyano, R., Vivo, J., Flores-Acuña, R., Molina, A., Blanco, C., Monterde, J.G. :
Purkinje cell apoptosis in arabian horses with cerebellar abiotrophy. J Vet Med A Physiol Pathol Clin Med 53:286-7, 2006. Pubmed reference: 16901270. DOI: 10.1111/j.1439-0442.2006.00836.x.
1995 Gerber, H., Gaillard, C., Fatzer, R., Marti, E., Pfistner, B., Sustronck, B., Ueltschi, G., Meier, H.P., Herholz, C., Straub, R., Geissbuhler, U., Gerber, V. :
Cerebellar abiotrophy in pure-bred arabians [German] Pferdeheilkunde 11:423-431, 1995.
1987 DeBowes, R.M., Leipold, H.W., Turner-Beatty, M. :
Cerebellar abiotrophy. Vet Clin North Am Equine Pract 3:345-52, 1987. Pubmed reference: 3497695.
1974 Baird, J.D., Mackenzie, C.D. :
Cerebellar hypoplasia and degeneration in part Arab horses Australian Veterinary Journal 50:25-28, 1974. Pubmed reference: 4819469.
1973 Palmer, A.C., Blakemore, W.F., Cook, W.R., Platt, H., Whitwell, K.E. :
Cerebellar hypoplasia and degeneration in the young Arab horses: clinical and neuropathological features Veterinary Record 93:62-66, 1973. Pubmed reference: 4748678.
1967 Sponseller, M. L. :
Proceedings of the American Association of Equine Practitioners Convention :123 only, 1967.
1966 Fraser, H. :
Two dissimilar types of cerebellar disorder in the horse. Vet Rec 78:608-12, 1966. Pubmed reference: 6005948.

Edit History


  • Created by Frank Nicholas on 17 Dec 2010
  • Changed by Frank Nicholas on 11 Sep 2011
  • Changed by Frank Nicholas on 09 Dec 2011
  • Changed by Frank Nicholas on 09 Apr 2019
  • Changed by Frank Nicholas on 11 Apr 2019