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Gene or Region: RAPGEF5
Reference Variant: C
Mutant Variant: A
Affected Breeds: Thoroughbred, Thoroughbred crosses, other Thoroughbred-influenced breeds
Research Confidence: High - Strong association in studied population
Explanation of Results: efih/efih = homozygous for Equine Familial Isolated Hypoparathyroidism, trait expressed efih/n = heterozygous for Equine Familial Isolated Hypoparathyroidism, carrier n/n = no variant detected
Equine Familial Isolated Hypoparathyroidism (EFIH) is a fatal genetic disorder identified in Thoroughbred foals, characterized by low blood calcium levels leading to muscle stiffness, seizures, and, ultimately, death. The condition is inherited in an autosomal recessive manner, meaning that foals with two copies of the causative genetic variant are affected.
EFIH manifests in foals up to 35 days old, presenting with symptoms such as involuntary muscle contractions, a stiff gait progressing to an inability to stand, seizures, fever, and rapid pulse. These clinical signs are associated with low blood calcium concentrations and inadequately low or normal parathyroid hormone levels. Necropsy findings often reveal underdeveloped or absent parathyroid glands.
The genetic basis for EFIH is a nonsense variant in the Rap Guanine Nucleotide Exchange Factor 5 gene (RAPGEF5) that replaces a serine in the protein product with a stop codon (c.2624C>A p.Ser875*), leading to a truncated protein with decreased functionality. RAPGEF5 plays a crucial role in intracellular signaling pathways, particularly those involved in cyclic AMP (cAMP)-dependent signaling and calcium homeostasis. In affected horses, this variant in RAPGEF5 disrupts normal parathyroid gland function, impairing PTH synthesis and secretion.
Rivas, V. N., Magdesian, K. G., Fagan, S., Slovis, N. M., Luethy, D., Javsicas, L. H., Caserto, B. G., Miller, A. D., Dahlgren, A. R., Peterson, J., Hales, E. N., Peng, S., Watson, K. D., Khokha, M. K., & Finno, C. J. (2020). A nonsense variant in Rap Guanine Nucleotide Exchange Factor 5 (RAPGEF5) is associated with equine familial isolated hypoparathyroidism in Thoroughbred foals. PLoS Genetics, 16(9), e1009028. doi: 10.1371/journal.pgen.1009028
Lordosis (L1, L2, L3, L4), also known as "Swayback", is a curvature or dip in the spine that is often seen in older horses. However, in the American Saddlebred, this condition also affects younger horses. These animals do not appear to experience pain from their condition and are still able to be used under saddle.
Malignant hyperthermia (MH) is a muscle disorder in which anesthesia, stress, or extreme exercise trigger a hyperthermic state. Symptoms include high temperature, increased heart rate, high blood pressure, sweating, acidosis, and muscle rigidity. If symptoms are not immediately resolved, death is likely to occur.
Myosin-Heavy Chain Myopathy (MY; previously "IMM") is a genetic muscle disease found most commonly in stock-type horses that can result in two different presentations, Immune-Mediated Myositis (IMM) and Nonexertional Rhabdomyolysis “tying up,” which are both characterized by muscle damage or loss. Both presentations are associated with the same genetic variant. Horses with MYHM may exhibit one or both presentations at different times in their lives, although some horses carrying the variant might not display any symptoms at all.
Myotonia (MYT) is a rare disorder involving a slowed relaxation of muscles after contraction. The most well-known example of myotonia is “fainting goats,” a breed that is characterized by sudden rigidy and/or falling over when startled. In the single documented horse, this resulted in a protruding third eyelid when excited, as well as problems with muscle stiffness.
