Defining Trends in Global Gene Expression in Arabian Horses with Cerebellar Abiotrophy

Abstract

Equine cerebellar abiotrophy (CA) is a hereditary neurodegenerative disease that affects the Purkinje neurons of the cerebellum and causes ataxia in Arabian foals. Signs of CA are typically first recognized either at birth to any time up to 6 months of age. CA is inherited as an autosomal recessive trait and is associated with a single nucleotide polymorphism (SNP) on equine chromosome 2 (13074277G>A), located in the fourth exon of TOE1 and in proximity to MUTYH on the antisense strand. We hypothesize that unraveling the functional consequences of the CA SNP using RNA-seq will elucidate the molecular pathways underlying the CA phenotype. RNA-seq (100 bp PE strand-specific) was performed in cerebellar tissue from four CA-affected and five age-matched unaffected horses. 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 (Log2(foldchange)=0.92, p=0.66) and MUTYH (Log2(foldchange)=1.13, p=0.66) were not differentially expressed. Among the major pathways that were differentially expressed, genes associated with calcium homeostasis and specifically expressed in Purkinje neurons, CALB1 (Log2(foldchange)= −1.7, p<0.01) and CA8 (Log2(foldchange)= −0.97, p<0.01), were significantly down-regulated, confirming loss of Purkinje neurons. There was also a significant up-regulation of markers for microglial phagocytosis, TYROBP (Log2(foldchange)= 1.99, p<0.01) and TREM2 (Log2(foldchange)= 2.02, p<0.01). 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.

Investigation of Known Genetic Mutations of Arabian Horses in Egyptian Arabian Foals with Juvenile Idiopathic Epilepsy

“…Cerebellar abiotrophy is inherited as an autosomal recessive trait and is associated with a single‐nucleotide polymorphism on chromosome 2 (13074277G>A), located in the 4th exon of TOE1 and in proximity to MUTYH on the antisense strand . This mutation results in loss of Purkinje neurons with secondary loss of the granular cell layer of the cerebellum . Signs can be recognized at birth or up to a few months of age and include ataxia, hypermetria, intention tremors, and lack of menace response .…”

“…35 This mutation results in loss of Purkinje neurons with secondary loss of the granular cell layer of the cerebellum. 25,36 Signs can be recognized at birth or up to a few months of age and include ataxia, hypermetria, intention tremors, and lack of menace response. 36 The prevalence of CA in a population of Arabian horses in South Africa was estimated to be 5.1%.…”

“…Genetic disorders have been reported in various pure‐bred horses . Disorders caused by known genetic mutations that are present in Arabian horses include lavender foal syndrome (LFS), cerebellar abiotrophy (CA), severe combined immunodeficiency (SCID), and occipitoatlantoaxial malformation (OAAM1) . Lavender foal syndrome is a lethal disorder of Egyptian Arabian foals characterized by foals born with a dilute coat color and profound neurologic dysfunction .…”

“…1 Genetic disorders have been reported in various pure-bred horses. 18 [19][20][21][22][23][24][25][26][27] Lavender foal syndrome is a lethal disorder of Egyptian Arabian foals characterized by foals born with a dilute coat color and profound neurologic dysfunction. [19][20][21] It is an autosomal recessive inherited disorder caused by a frameshift mutation in exon 30 of the myosin Va gene (MYO5A) that results in premature termination of transcription.…”

Cerebellar Purkinje cell degeneration in a mule foal (Equus mulus mulus)

“…The majority of the reports describing multiple cases of PCD have either suggested or established an autosomal recessive mode of inheritance through breeding studies, pedigree analysis or segregation analysis 3 15 17. Historically, PCD was considered a disease limited to the Arabian breed; however, a study showed that other breeds, which used Arabian progenitors as breeding stock, are also at risk of developing the disease 16.…”