TOE1 (cerebellar abiotrophy)

Crossing two of them

Its gene carrot

There is none. A disorder locus sets hasGeneCarrot() false — forcing one onto somebody’s line is hostile — and SpliceSafety keeps it out of the random splice as well, derived from the fact that it declares a non-informational Condition rather than from any hand-written list.

Gene key

horsegenetics.toe1

Priority

98

Alleles

ca N

Outcomes

wild, toe1-carrier, cerebellar-abiotrophy

Coat effect

none — every outcome is a wild type

Default allele

N

Wild population

2.4% of founders carry one copy; none carries two

Founder draws

1 × nextFloat()

Catalogue entries

1 — it never changes what a horse looks like

The combination table

The heaviest jump penalty in the mod

And the only disorder where that is the headline symptom rather than a side effect of being generally unwell. A CA horse cannot judge a distance, so this is the one locus whose cost a player feels through the reins rather than reads in a panel — which makes it the most legible disorder here despite being invisible.

Progressive, which needs an age model the mod does not have

A real CA foal looks normal and worsens over its first months. Horse aging is deliberately out of scope (see gap 1, where grey ran into the same wall), so there is no clock for an onset to run on and the cost is flat from birth.

Grey solved its version of this by reading copy-number dosage for a progression window and letting the horse’s own epigenetics pick a point in it, fixed for life. The same trick would work here if the severity model ever lands — a CA horse would be born somewhere on a spectrum rather than moving along one.

What abiotrophy means

Abiotrophy is the premature degeneration of cells that formed normally and then fail to survive. In equine CA the cells are the Purkinje neurons of the cerebellum.

The cerebellum does not generate strength or willingness to move. It makes movement controlled and accurate: balance, posture, timing, precision, motor learning, rapid adjustment of body position. So when Purkinje cells die, the horse keeps its muscle power and loses the ability to aim it. That is the whole character of the disorder, and it is why the mod’s heaviest jump penalty sits on this gene rather than its heaviest health penalty.

CA foals can look normal at birth. Signs usually appear from about 6 weeks to 4 months, with onset ranging from birth to around six months, and severity varies a great deal — some foals are profoundly ataxic, others show little more than an intention head tremor. Scott et al., PMC5336519

Gene, variant, locus

The original mapping narrowed CA to an approximately 142 kb region on the p arm of chromosome 2. The associated SNP is in exon 4 and produces an arginine-to-histidine substitution at amino acid 95, in a highly conserved region of the protein. OMIA 000175

TOE1 encodes an RNA-processing protein — a 3′ exonuclease/deadenylase working on small nuclear RNA, in Cajal bodies and cytoplasmic P-bodies, structures that matter for RNA maturation, RNA turnover and gene-expression regulation. In humans, biallelic loss-of-function TOE1 variants cause pontocerebellar hypoplasia, which is what makes TOE1 a persuasive neurological candidate in the horse.

Why “the TOE1 gene” is a slight shortcut

The test is legitimately called TOE1 CA, and the mechanism is not fully settled. The SNP sits in two genomic contexts at once: it is a coding missense change in TOE1, and it is about 1,200 base pairs upstream of the start of MUTYH on the opposite strand, near a predicted GATA2 transcription-factor binding site in the MUTYH regulatory region.

MUTYH encodes a DNA glycosylase that repairs oxidative DNA damage including 8-oxoguanine lesions — an early and compelling candidate, since failing oxidative-damage repair could plausibly endanger metabolically active developing neurons.

So the honest description is a highly concordant, likely causal or causally informative variant inside a complex overlapping TOE1–MUTYH neighbourhood — not a fully dissected molecular pathway. The mod names the gene horsegenetics.toe1 and inherits that shortcut; the alternative naming problem is the one CVM has, from the opposite direction.

The lesion

Postnatal degeneration and apoptosis of cerebellar Purkinje neurons. Purkinje cells are the sole output neurons of the cerebellar cortex, so losing them disrupts cerebellar signalling even when the rest of the nervous system and the musculature look grossly normal. Affected cerebella show depletion of Purkinje neurons, disorganisation of the normal three-layer cortical architecture, secondary effects on granular neurons, increased Bergmann glial changes, and activation of microglial phagocytic pathways clearing dying cells.

RNA sequencing found reduced expression of Purkinje-neuron and calcium-homeostasis markers including CALB1 and CA8 in affected tissue, and increased expression of microglial phagocytosis genes including TYROBP and TREM2. Those are best read as the molecular footprint of Purkinje-cell loss and neuroinflammatory cleanup, not as the mutation’s direct action.

Clinical signs

Cerebellar ataxia — uncoordinated movement from loss of central motor coordination, not from weakness. What is seen:

• Intention head tremor, most obvious during focused purposeful movement such as reaching toward feed.
• A wide-based stance compensating for poor equilibrium.
• Exaggerated, high, paddling forelimb action.
• Hypermetric steps — overreaching or poorly measured limb placement.
• Swaying, stumbling, startling easily, falling.
• Difficulty rising after lying down.
• Poor quick balance corrections.
• Reduced or absent menace response despite intact vision, in some horses.

A CA foal may have normal curiosity, appetite and apparent strength, and then oversteps, sways, falls or struggles to rise when it turns sharply, crosses uneven ground, is startled, or tries to correct its balance. That is why early CA gets mistaken for injury, a previous fall, weakness, poor handling or an orthopaedic problem.

Coat, build, size

No established effect on coat colour or pigment production, grey, white spotting, dilution or appaloosa patterning, mane and tail quantity or hair texture, mature height, body mass, muscling or ordinary conformation, hoof colour or quality, or reproductive phenotype in clinically normal carriers. A CA foal can be any colour its parents could produce; the allele is unrelated to MC1R, ASIP, KIT, STX17, SLC45A2, PMEL and MITF.

CA is not a dwarfism or a conformation disease. Affected horses may pick up scrapes, bruises, abnormal posture or reduced condition from falls and restricted activity — consequences of the neurology, not evidence that the mutation makes a horse short or badly made.

Speed, jumping, athletic use

Affected horses. CA is incompatible with safe athletic use. Even a mildly affected horse can have unpredictable balance failure, poor limb placement, an exaggerated gait and heightened injury risk. UC Davis notes clinically affected horses are often euthanised or limited to pasture-pet status because they never become coordinated enough to ride safely. UC Davis VGL

Carriers. No reliable evidence of altered speed, stamina, jumping talent, gait quality, trainability, muscle power, coordination, size, conformation or general health. A carrier is expected to be neurologically normal, and the concern is reproductive. Claims that carriers are delicate, unusually athletic, less coordinated, more reactive or visibly identifiable are unsupported: a carrier cannot be picked out by look, movement, colour, pedigree prestige or performance record.

Inheritance

Autosomal, so mares and stallions carry equally. A carrier pairing gives 25% / 50% / 25%, per foal independently, and a carrier crossed to a clear mate cannot produce an affected foal though about half the foals will carry.

Breeds and frequency

CA occurs almost exclusively in Arabians and Arabian-derived populations, and is one of the core diseases on Arabian health panels. The largest screening figure comes from UC Davis testing of nearly 11,000 horses: an estimated average Arabian carrier frequency of about 20%. That is an aggregate screening estimate, not a current value for every registry, country, family or programme.

Twenty percent carriers corresponds to roughly a 10% allele frequency under Hardy-Weinberg, which would imply about 1% homozygotes under random mating with no selection. Observed CA foal frequency differs, because breeders avoid carrier matings once testing exists, affected foals die or are euthanised, and populations do not mate at random.

The allele largely entered non-Arabian populations through Arabian ancestry, which is why the advice is to test horses with Arabian ancestors rather than horses of a particular breed. CA and the tested allele have also been recorded in Arabian crosses and in curated disease records for Quarter Horses and Icelandic Horses — which is not evidence that CA is common in those breeds, and is exactly why ancestry and direct testing beat breed labels.

The mod’s WILD_CARRIER_PERCENT is 2.4, against ~20% in Arabians — the widest gap of any gene on the health layer, and the same distance artefact as the rest: a world-wide founder rate standing where a breed-specific one belongs.

What is settled, and what is not

Established. CA is an autosomal recessive neurological disorder; the validated SNP is on ECA2 in exon 4 of TOE1 and causes p.Arg95His; it was highly concordant with CA in the original Arabian studies; the defining pathology is postnatal Purkinje-cell degeneration; the outcome is ataxia, tremor, exaggerated gait, balance deficits, falls and unsafe athletic use; and the variant is common enough in Arabians to warrant routine testing.

Plausible but unresolved. Whether p.Arg95His directly impairs TOE1’s RNA-processing function in Purkinje-cell maturation; whether the SNP also changes MUTYH transcription or oxidative-repair capacity at a key developmental moment; why onset and severity differ between affected horses; whether granular neuron changes are consistently secondary; and why a few affected horses show no easily recognised signs.

Unsupported. That CA changes coat colour, sheen, height, build or conformation; that carriers are visibly recognisable or poor performers; that carriers have any speed, endurance, jump or gait advantage; or that a horse which looks normal, performs well, or has an unaffected parent must be genetically clear.