In other species: pig , golden hamster

Categories: Immune system phene

Links to possible relevant human trait(s) and/or gene(s) in OMIM: 300400 (trait) , 308380 (gene) , 312863 (trait)

Links to relevant human diseases in MONDO:

• MONDO:0010730: combined immunodeficiency, X-linked

Mendelian trait/disorder: yes

Mode of inheritance: X-linked

Disease-related: yes

Key variant known: yes

Year key variant first reported: 1994

Species-specific symbol: XSCID

Species-specific description: X-linked severe combined immunodeficiency disease (XSCID) is an immune disorder of basset hounds and Cardigan Welsh corgis. Affected pups have peripheral lymphopenia, with low or absent IgG and IgA, but normal IgM concentrations. Clinical findings include the absence of palpable lymph nodes, a small thymic shadow on radiographs, and chronic recurrent infections. It is invariably lethal. The breed specific mutations in IL2RG lead to production of a truncated protein. Edited by Paula Henthorn, PhD

Mapping: CFX (Deschenes et al. 1994)

Molecular basis: By cloning and sequencing a very likely comparative candidate gene (based on the homologous human disorder), Henthorn et al. (1994) showed that the causative mutation in basset hounds is a four nucleotide deletion causing a frame shift and subsequent premature termination of the gene coding for the gamma chain of the IL-2 receptor. The causative mutation in the Cardigan Welsh corgi is a single nucleotide insertion causing a frameshift and subsequent premature termination of the gene encoding the gamma chain of the IL-2 receptor (Somberg et al., 1995). There is an analogous disease in humans (OMIM# 300400).

Clinical features: Affected pups are characterized by failure to thrive, absence of palpable peripheral lymph nodes, small thymic size, and T cells that are unresponsive to proliferative stimulation. Affected pups often succumb to chronic, recurrent, opportunistic infections in varied locations (ear, skin, intestine). Other signs include diarrhea, and intermittent vomiting. Vaccination of affected pups with modified live virus vaccines can induce viremia and clinical signs. Affected pups have peripheral lymphopenia with a normal percentage of B cells and a low to normal percentage of T cells. IgM concentrations are normal, but IgG and IgA concentrations are greatly reduced or absent (Pullen et al., 1997). Even with supportive treatment, affected pups usually die by 4 months of age.

Pathology: IL2RG encodes the common gamma chain, which is a subunit of the receptors for IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21. Functional receptors for these cytokines are necessary for leukocyte proliferation, differentiation, survival and function, and their absence causes a severe and ultimately lethal disease (Kennedy et al., 2011). T cells in affected animals do not proliferate in response to mitogens, such as phytohemagglutin (PHA), because they do not express a functional IL-2 receptor. B cells can produce IgM but cannot class switch to IgG (Felsburg et al, 1999). Primary and secondary lymphoid tissue is either reduced in size or totally absent. At necropsy, the thymus is small and dysplastic (Felsburg et al., 1999).

Prevalence: This disorder is rare.

Control: This is an X-linked trait causing severe disease in very young affected males. Thus, the disease reported in both breeds was likely recognized within a few generations of the occurrence of the initial causative mutation (Pullen et al., 1997). Consequently, the mutation was never widely disseminated in either breed, and breed wide testing is not indicated. However, new cases can occur in any breed due to novel mutations. Rapid referral to a specialist is recommended for suspected cases. Female relatives of affected males should be tested to identify carriers. Breeding of carrier females is not recommended. However, males that are free of the disease do not carry the mutation and can be bred.

Genetic testing: There is a PCR-based test available to detect the mutation in the basset hound and the Cardigan Welsh Corgi.

Breeds: Basset Hound (Dog) (VBO_0200126), Cardigan Welsh Corgi (Dog) (VBO_0200290).
Breeds in which the phene has been documented. (If a likely causal variant has been documented for the phene, see the variant table breeds in which the variant has been reported).

Associated gene: