OMIA 000899-9615 : Severe combined immunodeficiency disease, X-linked in Canis lupus familiaris

In other species: pig

Possibly relevant human trait(s) and/or gene(s)s (MIM numbers): 300400 , 308380 , 312863

Mendelian trait/disorder: yes

Mode of inheritance: X-linked

Considered a defect: 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, Cardigan Welsh Corgi.

Associated gene:

Symbol Description Species Chr Location OMIA gene details page Other Links
IL2RG interleukin 2 receptor, gamma Canis lupus familiaris X NC_006621.3 (55488485..55480846) IL2RG Homologene, Ensembl, NCBI gene

Variants

By default, variants are sorted chronologically by year of publication, to provide a historical perspective. Readers can re-sort on any column by clicking on the column header. Click it again to sort in a descending order. To create a multiple-field sort, hold down Shift while clicking on the second, third etc relevant column headers.

WARNING! Inclusion of a variant in this table does not automatically mean that it should be used for DNA testing. Anyone contemplating the use of any of these variants for DNA testing should examine critically the relevant evidence (especially in breeds other than the breed in which the variant was first described). If it is decided to proceed, the location and orientation of the variant sequence should be checked very carefully.

Breed(s) Variant Phenotype Gene Allele Type of Variant Reference Sequence Chr. g. or m. c. or n. p. Verbal Description EVA ID Year Published PubMed ID(s) Acknowledgements
Basset Hound Severe combined immunodeficiency disease, X-linked IL2RG deletion, small (<=20) 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 1994 7829104
Cardigan Welsh Corgi Severe combined immunodeficiency disease, X-linked IL2RG insertion, small (<=20) a single nucleotide insertion causing a frameshift 1995 8571541

References


Note: the references are listed in reverse chronological order (from the most recent year to the earliest year), and alphabetically by first author within a year.
2011 Kennedy, DR., Hartnett, BJ., Kennedy, JS., Vernau, W., Moore, PF., O'Malley, T., Burkly, LC., Henthorn, PS., Felsburg, PJ. :
Ex vivo γ-retroviral gene therapy of dogs with X-linked severe combined immunodeficiency and the development of a thymic T cell lymphoma. Vet Immunol Immunopathol 142:36-48, 2011. Pubmed reference: 21536334. DOI: 10.1016/j.vetimm.2011.04.003.
2009 Kennedy, DR., McLellan, K., Moore, PF., Henthorn, PS., Felsburg, PJ. :
Effect of ex vivo culture of CD34+ bone marrow cells on immune reconstitution of XSCID dogs following allogeneic bone marrow transplantation. Biol Blood Marrow Transplant 15:662-70, 2009. Pubmed reference: 19450750. DOI: 10.1016/j.bbmt.2009.03.014.
2007 Suter, SE., Gouthro, TA., O'Malley, T., Hartnett, BJ., McSweeney, PA., Moore, PF., Felsburg, PJ., Haskins, ME., Henthorn, PS. :
Marking of peripheral T-lymphocytes by retroviral transduction and transplantation of CD34+ cells in a canine X-linked severe combined immunodeficiency model. Vet Immunol Immunopathol 117:183-96, 2007. Pubmed reference: 17442404. DOI: 10.1016/j.vetimm.2007.03.004.
Vernau, W., Hartnett, BJ., Kennedy, DR., Moore, PF., Henthorn, PS., Weinberg, KI., Felsburg, PJ. :
T cell repertoire development in XSCID dogs following nonconditioned allogeneic bone marrow transplantation. Biol Blood Marrow Transplant 13:1005-15, 2007. Pubmed reference: 17697962. DOI: 10.1016/j.bbmt.2007.05.013.
2006 Goldschmidt, MH., Kennedy, JS., Kennedy, DR., Yuan, H., Holt, DE., Casal, ML., Traas, AM., Mauldin, EA., Moore, PF., Henthorn, PS., Hartnett, BJ., Weinberg, KI., Schlegel, R., Felsburg, PJ. :
Severe papillomavirus infection progressing to metastatic squamous cell carcinoma in bone marrow-transplanted X-linked SCID dogs. J Virol 80:6621-8, 2006. Pubmed reference: 16775349. DOI: 10.1128/JVI.02571-05.
Ting-De Ravin, SS., Kennedy, DR., Naumann, N., Kennedy, JS., Choi, U., Hartnett, BJ., Linton, GF., Whiting-Theobald, NL., Moore, PF., Vernau, W., Malech, HL., Felsburg, PJ. :
Correction of canine X-linked severe combined immunodeficiency by in vivo retroviral gene therapy. Blood 107:3091-7, 2006. Pubmed reference: 16384923. DOI: 10.1182/blood-2005-10-4057.
2004 Perryman, L.E. :
Molecular pathology of severe combined immunodeficiency in mice, horses, and dogs. Vet Pathol 41:95-100, 2004. Pubmed reference: 15017021. DOI: 10.1354/vp.41-2-95.
2000 Hartnett, B.J., Somberg, R.L., Krakowka, S., Ochs, H.D., HogenEsch, H., Moore, P.F., Weinberg, K.I., Felsburg, P.J. :
B-cell function in canine X-linked severe combined immunodeficiency Veterinary Immunology & Immunopathology 75:121-134, 2000.
1999 Felsburg, P.J., Hartnett, B.J., Henthorn, P.S., Moore, P.F., Krakowka, S., Ochs, H.D. :
Canine X-linked severe combined immunodeficiency Veterinary Immunology & Immunopathology 69:127-135, 1999.
Hartnett, B.J., Henthorn, P.S., Moore, P.F., Weinberg, K.I., Ochs, H.D., Felsburg, P.J. :
Bone marrow transplantation for canine X-linked severe combined immunodeficiency Veterinary Immunology & Immunopathology 69:137-144, 1999.
1998 Felsburg, P.J., Somberg, R.L., Hartnett, B.J., Henthorn, P.S., Carding, S.R. :
Canine X-linked severe combined immunodeficiency Immunologic Research 17:63-73, 1998. Pubmed reference: 9479568. DOI: 10.1007/BF02786431.
1997 Felsburg, P.J., Somberg, R.L., Hartnett, B.J., Suter, S.F., Henthorn, P.S., Moore, P.F., Weinberg, K.I., Ochs, H.D. :
Full immunologic reconstitution following nonconditioned bone marrow transplantation for canine X-linked severe combined immunodeficiency Blood 90:3214-3221, 1997. Pubmed reference: 9376605.
Pullen, R.P., Somberg, R.L., Felsburg, P.J., Henthorn, P.S. :
X-linked severe combined immunodeficiency in a family of cardigan welsh corgis Journal of the American Animal Hospital Association 33:494-499, 1997. Pubmed reference: 9358416.
1996 Somberg, R.L., Tipold, A., Hartnett, B.J., Moore, P.F., Henthorn, P.S., Felsburg, P.J. :
Postnatal development of T cells in dogs with X-linked severe combined immunodeficiency Journal of Immunology 156:1431-1435, 1996.
1995 Somberg, R.L., Pullen, R.P., Casal, M.L., Patterson, D.F., Felsburg, P.J., Henthorn, P.S. :
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, 1995. Pubmed reference: 8571541.
1994 Deschenes, S.M., Puck, J.M., Dutra, A.S., Somberg, R.L., Felsburg, P.J., Henthorn, P.S. :
Comparative mapping of canine and human proximal Xq and genetic analysis of canine X-linked severe combined immunodeficiency Genomics 23:62-68, 1994. Pubmed reference: 7829103. DOI: 10.1006/geno.1994.1459.
Henthorn, P.S., Somberg, R.L., Fimiani, V.M., Puck, J.M., Patterson, D.F., Felsburg, P.J. :
IL-2R gamma gene microdeletion demonstrates that canine X- linked severe combined immunodeficiency is a homologue of the human disease Genomics 23:69-74, 1994. Pubmed reference: 7829104. DOI: 10.1006/geno.1994.1460.
Somberg, R.L., Robinson, J.P., Felsburg, P.J. :
T lymphocyte development and function in dogs with X-linked severe combined immunodeficiency Journal of Immunology 153:4006-4015, 1994.
1993 Snyder, P.W., Kazacos, E.A., Felsburg, P.J. :
Histologic Characterization of the Thymus in Canine X-Linked Severe Combined Immunodeficiency Clinical Immunology and Immunopathology 67:55-67, 1993. Pubmed reference: 8443985.
1992 Felsburg, P.J., Somberg, R.L., Perryman, L.E. :
Domestic animal models of severe combined immunodeficiency: canine X-linked severe combined immunodeficiency and severe combined immunodeficiency in horses. Immunodefic Rev 3:277-303, 1992. Pubmed reference: 1449787.
1989 Jezyk, PF., Felsburg, PJ., Haskins, ME., Patterson, DF. :
X-linked severe combined immunodeficiency in the dog. Clin Immunol Immunopathol 52:173-89, 1989. Pubmed reference: 2736807.

Edit History


  • Created by Frank Nicholas on 28 Aug 2006
  • Changed by Martha MaloneyHuss on 02 Sep 2011
  • Changed by Vicki Meyers-Wallen on 19 Sep 2011
  • Changed by Frank Nicholas on 12 Dec 2011
  • Changed by Frank Nicholas on 31 Aug 2012