Familial neonatal hypoparathyroidism

Gene: RAPGEF5

Transmission: Autosomal recessive

For an autosomal recessive genetic disease an animal must have two copies of the mutation in question to be at risk of developing the disease. Both parents of an affected animal must be carriers of at least one copy of the mutation. Animals that have only one copy of the mutation are not at risk of developing the disease but are carrier animals that can pass the mutation on to future generations.

Mutation: Substitution, RAPGEF gene; c.2624 C>A, p.(Ser875 STOP), exon 6, chr.4.

Medical system: Endocrine

Breeds: Thoroughbred

Age of onset of symptoms: Shortly after birth.

A fatal disease of neonatal hypocalcemia is described in Thoroughbred foals.  Clinical signs include hypocalcemia as well muscle rigidity (tetany), tachycardia, excessive sweating (hyperhidrosis) and diharrea.  Although intravenous calcium solutions can give temporary relief from symptoms to some animals, cases end with death or euthanasia.  Necropsy demonstrates an agenesis of the parathyroid gland.  Molecular studies revealed a homozygous mutation in the RAPGEF5 gene as being responsible for the disease.  The RAPGEF gene codes for a protein involved in the WNT/b-catenin signaling pathway which is important for developmental decisions and also important for calcium homeostasis; expression of the RAPGEF gene is particularly high within the parathyroid gland.  The calculated frequency of carriers (M/N) for the RAPGEF5 mutation within Thoroughbreds is 1.6%.

References:

OMIA link: [2458-9796]

Elcombe ME, Bellone RR, Magdesian KG, Finno CJ. (2022) Prevalence of the RAPGEF5 c.2624C>A and PLOD1 c.2032G>A variants associated with equine familial isolated hypoparathyroidism and fragile foal syndrome in the US Thoroughbred population (1988-2019). Equine Vet J 55(4) : 666-671.  [pm/36199159]

Rivas VN, Magdesian KG, Fagan S, et al. (2020) A nonsense variant in Rap Guanine Nucleotide Exchange Factor 5 (RAPGEF5) is associated with equine familial isolated hypoparathyroidism in Thoroughbred foals. PLoS Genet 16:e1009028.  [pm/32986719]

Beyer MJ, Freestone JF, Reimer JM, et al. (1997) Idiopathic hypocalcemia in foals. J Vet Intern Med 11(6):356-60.  [pm/9470161]

Contributed by: Mégane Demers and Marie Ladet, Class of 2028, Faculty of Veterinary Medicine, University of Montreal.