X-linked severe combined immunodeficiency, XSCID (IL2RG-related)

 

Gene: IL2RG

Transmission: X chromosome linked, recessive

For an X-linked recessive genetic disease, a male must have one copy of the mutation in question to be at risk of developing the disease.  All affected males transmit the mutation to all the females of their offspring.  A female must have two copies of the mutation in question to be at risk of developing the disease.  Females with 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.

Mutations:

Basset Hound mutation: Deletion, IL2RG gene: c.30_33 del., p.(Leu11Tyr frameshift), Chr.X.

Cardigan Welsh Corgi mutation: Insertion, IL2RG gene: c.583_584 ins.C, p.(Arg195Pro frameshift STOP 5), Chr.X.

Medical system: Blood, immune

Breed: Basset Hound, Cardigan Welsh Corgi

Age of onset of symptoms: From 6 to 8 weeks

Severe X-linked combined immunodeficiency (XSCID) is a serious genetic disorder affecting the development of the immune system that has been reported in several dog breeds. Affected puppies appear normal at birth but rapidly develop stunted growth and marked susceptibility to infections as maternal immunity declines. Infections are frequent, severe, and recurrent, primarily affecting the skin, respiratory tract, and gastrointestinal tract. Immunologically, there is a near-complete absence of functional T cells, inadequate maturation of B cells, and severe thymus hypoplasia. Due to the immune system’s inability to respond adequately, the clinical course is rapid and leads to a fatal outcome within the first few months of life.

Molecular studies identified 2 mutations within the IL2RG gene as responsible for XSCID.  The IL2RG gene codes for the common gamma chain of a number of receptors on the surface of lymphocyte cells, mention the IL-2 receptor.  As a consequence, T-cells cannot proliferate and B-cells are blocked from producing the IgG and IgA classes of antibodies, resulting in the clinical symptoms of XSCID.

In general, sex-linked diseases are relatively easy to control within affected breeds. In the case of XSCID, although asymptomatic carrier females can pass the mutation and the disease to their male offspring, affected males do not pass the mutation further because of the severity of the disease.  The mutations reported for XSCID have been of academic interest for testing retroviral treatment protocols but are not of practical concern to dog breeders.  In a recent survey of mutation frequencies in dogs, 0 cases of the Basset Hound mutation were detected in 990 Basset Hounds tested, while 0 cases of the Corgi mutation were detected in 125 Cardigan Welsh Corgis tested.  Indeed, 0 cases of either mutation were detected in over 81,000 mixed breed dogs tested.

An autosomal version of SCID involving mutations in the PRKDC gene is also described for the dog, as well as for the horse.

 

References:

OMIA link: [0899-9615]

Donner J, Freyer J, Davison S, et al. (2023) Genetic prevalence and clinical relevance of canine Mendelian disease variants in over one million dogs.  PLoS Genet. 19(2):e1010651. [pubmed/36848397]

Felsburg PJ, Hartnett BJ, Henthorn PS, et al. (1999) Canine X-linked severe combined immunodeficiency Veterinary Immunology & Immunopathology 69:127-135. [pm/10507300]

Pullen RP, Somberg RL, Felsburg PJ, Henthorn, PS, et al. (1997) X-linked severe combined immunodeficiency in a family of cardigan welsh corgis. Journal of the American Animal Hospital Association 33:494-499. [pm/9358416]

Somberg RL, Pullen RP, Casal ML, et al. (1995) A single nucleotide insertion in the canine interleukin-2 receptor gamma chain results in X-linked severe combined immunodeficiency disease. Vet Immunol Immunopathol 47:203-13. [pm/8571541]

 

With contributions by: Maude Richard and Marie-Audrey Lahay, Class of 2030, Faculty of Veterinary Medicine, University of Montreal.  (Translation: DWS).