OMIA 000220-9796 : Severe combined immunodeficiency disease, autosomal in Equus caballus

In other species: dog

Possibly relevant human trait(s) and/or gene(s) (MIM number): 600899

Mendelian trait/disorder: yes

Mode of inheritance: Autosomal Recessive

Considered a defect: yes

Key variant known: yes

Year key variant first reported: 1997

Species-specific name: Severe Combined Immunodeficiency Disease (SCID)

History: This disorder was first described by McGuire and Poppie (1973), in two Arabian foals that were full siblings , each of which exhibited deficiency of B- and T-lymphocyte function. Further investigation of families indicated this was a recessive genetic disorder found among Arabian horses. Comparative functional candidate genes from human SCID (ADA, NP) were considered and rejected (McGuire et al. 1976 ) before the gene (PRKDC) and variant responsible for the trait was found. {with thanks to Meredith O’Connell, Tanya German, Isabella Pisani and Karalie Andrews, working under the guidance of Professor Ernie Bailey; 25 Feb 2019}

Mapping: Using 23 microsatellite markers on a carrier stallion and 19 affected offspring, Bailey et al. (1997) showed linkage of this disorder to the markers HTG8 and HTG4. Knowing that the DNAPK gene had recently been implicated in mouse SCID (Blunt et al., 1996; PNAS 93: 10285-90), these authors then used a somatic cell hybrid panel to show that the equine DNA-PK gene is syntenic with those same two microsatellite markers, thereby implicating DNAPK as a very strong candidate gene for equine SCID. By FISH analysis, they also showed that this gene physically maps to horse chromosome ECA9p12.

Molecular basis: The molecular basis of SCID in horses was discovered by Shin et al. (1997), who used the comparative candidate-gene approach (based on work with SCID mice; see Mapping section). By sequencing the equine homologue of DNAPK, Shin et al. (1997) showed that SCID in horses is due to a 5bp deletion giving rise to a frameshift in that gene, resulting in the lack of full-length kinase, and absence of kinase activity. The DNAPK gene was previously called DNA-PKcs; it is now called PRKDC (protein kinase, DNA-activated, catalytic polypeptide). The Ensembl Variant Effect Predictor (VEP) predicts the effect of this variant to be “high”. {with thanks to Meredith O’Connell, Tanya German, Isabella Pisani and Karalie Andrews, working under the guidance of Professor Ernie Bailey; 25 Feb 2019}

Clinical features: Affected foals are clinically normal at birth but beginning at about 10 days of age they develop a range of clinical signs, particularly bronchopneumonia and diarrhea with which adenoviruses are peculiarly associated (Studdert, 1978). {with thanks to Meredith O’Connell, Tanya German, Isabella Pisani and Karalie Andrews, working under the guidance of Professor Ernie Bailey; 25 Feb 2019}

The "combined" nature of this disorder was highlighted by McGuire and Poppie (1973): “The defect in the B-lymphocyte system was shown by hypogammaglobulinemia, lymphopenia and absence of germinal centers. The almost total absence of thymic tissue in one foal and the lack of thymic dependent lymphocytes in the spleens of both foals demonstrate a T-cell defect.” {with thanks to Professor E. Bailey; 20 March 2019}

Associated gene:

Symbol Description Species Chr Location OMIA gene details page Other Links
PRKDC protein kinase, DNA-activated, catalytic polypeptide Equus caballus 9 NC_009152.3 (36236670..36438603) PRKDC 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
Arabian Severe combined immunodeficiency disease, autosomal PRKDC deletion, small (<=20) Ecab3.0 9 g.36395752_36395759del c.9478_9482del p.N3160fs*3 A 5bp deletion giving rise to a frameshift in PRKDC The following details (from which the coordinate fields were populated) were provided by Meredith O’Connell, Tanya German, Isabella Pisani and Karalie Andrews, under the supervision of Professor Ernie Bailey. 20 Feb 2019 NC_009152.3 g.36395752-36395976del; NM_001163858 c.9478_9482del; NP_001157330 p.N3160fs*3 1997 9103416

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.
2014 [No authors listed] :
The Arabian horse SCIDs to a halt. Lab Anim (NY) 43:49, 2014. Pubmed reference: 24451352. DOI: 10.1038/laban.467.
Tarr, C.J., Thompson, P.N., Guthrie, A.J., Harper, C.K. :
The carrier prevalence of severe combined immunodeficiency, lavender foal syndrome and cerebellar abiotrophy in Arabian horses in South Africa. Equine Vet J 46:512-4, 2014. Pubmed reference: 24033554. DOI: 10.1111/evj.12177.
2011 Larson, J., Buechner-Maxwell, V., Crisman, M.V., LeRoith, T., Witonsky, S. :
Severe combined immunodeficiency in a Caspian filly. J Vet Intern Med 25:954-8, 2011. Pubmed reference: 21736619. DOI: 10.1111/j.1939-1676.2011.0746.x.
2008 Crisman, M.V., Scarratt, W.K. :
Immunodeficiency disorders in horses. Vet Clin North Am Equine Pract 24:299-310, vi, 2008. Pubmed reference: 18652957. DOI: 10.1016/j.cveq.2008.03.003.
Piro, M., Benjouad, A., Tligui, N.S., El Allali, K., El Kohen, M., Nabich, A., Ouragh, L. :
Frequency of the severe combined immunodeficiency disease gene among horses in Morocco. Equine Vet J 40:590-1, 2008. Pubmed reference: 19031514.
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.
2002 Ding, Q., Bramble, L., Yuzbasiyan-Gurkan, V., Bell, T., Meek, K. :
DNA-PKcs mutations in dogs and horses: allele frequency and association with neoplasia Gene 283:263-269, 2002. Pubmed reference: 11867233.
2000 Don-van't, Slot, H.P., van, der, Kolk, J.H. :
Severe-Combined-Immunodeficiency-Disease (SCID) in the Arabian horse: a review [Review] [Dutch] Tijdschrift voor Diergeneeskunde 125:577-581, 2000. Pubmed reference: 11042889.
Perryman, L.E. :
Primary immunodeficiencies of horses. Vet Clin North Am Equine Pract 16:105-16, vii, 2000. Pubmed reference: 10752141.
Richards, AJ., Kelly, DF., Knottenbelt, DC., Cheeseman, MT., Dixon, JB. :
Anaemia, diarrhoea and opportunistic infections in Fell ponies. Equine Vet J 32:386-91, 2000. Pubmed reference: 11037259.
Shin, E.K., Rijkers, T., Pastink, A., Meek, K. :
Analyses of TCRB rearrangements substantiate a profound deficit in recombination signal sequence joining in SCID foals: Implications for the role of DNA-dependent protein kinase in V(D)J recombination Journal of Immunology 164:1416-1424, 2000.
1999 Mair, T.S. :
Clinical snapshot - Case presentation #7 - Combined immunodeficiency syndrome (CID) Compendium on Continuing Education for the Practicing Veterinarian 21:659-+, 1999.
Swinburne, J., Lockhart, L., Scott, M., Binns, M.M. :
Estimation of the prevalence of severe combined immunodeficiency disease in UK Arab horses as determined by a DNA-based test Veterinary Record 145:22-23, 1999. Pubmed reference: 10452394.
1998 Bernoco, D., Bailey, E. :
Frequency of the SCID gene among Arabian horses in the USA Animal Genetics 29:41-42, 1998. Pubmed reference: 9682449.
Leber, R., Wiler, R., Perryman, L.E., Meek, K. :
Equine SCID: mechanistic analysis and comparison with murine SCID. Vet Immunol Immunopathol 65:1-9, 1998. Pubmed reference: 9802572.
1997 Bailey, E., Reid, R.C., Skow, L.C., Mathiason, K., Lear, T.L., Mcguire, T.C. :
Linkage of the gene for equine combined immunodeficiency disease to microsatellite markers HTG8 and HTG4 - synteny and FISH mapping to ECA9 Animal Genetics 28:268-273, 1997. Pubmed reference: 9345723.
Jones, W.E. :
Severe combined immunodeficiency now a solution Journal of Equine Veterinary Science 17:630-632, 1997.
Shin, E.K., Perryman, L.E., Meek, K. :
A kinase-negative mutation of DNA-PK(CS) in equine SCID results in defective coding and signal joint formation. J Immunol 158:3565-9, 1997. Pubmed reference: 9103416.
Shin, E.K., Perryman, L.E., Meek, K. :
Evaluation of a test for identification of Arabian horses heterozygous for the severe combined immunodeficiency trait. J Am Vet Med Assoc 211:1268-70, 1997. Pubmed reference: 9373363.
1995 Lunn, D.P., Mcclure, J.T., Schobert, C.S., Holmes, M.A. :
Abnormal patterns of equine leucocyte differentiation antigen expression in severe combined immunodeficiency foals suggests the phenotype of normal equine natural killer cells Immunology 84:495-499, 1995. Pubmed reference: 7751035.
Wiler, R., Leber, R., Moore, B.B., Vandyk, L.F., Perryman, L.E., Meek, K. :
Equine severe combined immunodeficiency - a defect in V(D)J recombination and DNA-dependent protein kinase activity Proceedings of the National Academy of Sciences of the United States of America 92:11485-11489, 1995. Pubmed reference: 8524788.
1994 Kettler, M.K., Weil, M.R., Mascotti, K., Perryman, L.E. :
Serum Hypoxanthine and Xanthine Concentrations in Horses Heterozygous for Combined Immunodeficiency Journal of Animal Breeding and Genetics - Zeitschrift Fur Tierzuchtung und Zuchtungsbiologie 111:148-151, 1994.
1993 Anon. :
New Findings in Cid Study Journal of Equine Veterinary Science 13:658, 1993.
Balson, G.A., Croy, B.A., Ross, T.L., Yager, J.A. :
Demonstration of equine immunoglobulin in sera from severe combined immunodeficiency/beige mice inoculated with equine lymphocytes. Vet Immunol Immunopathol 39:315-25, 1993. Pubmed reference: 8116213.
Prescott, J.F. :
Immunodeficiency and Serious Pneumonia in Foals - The Plot Thickens Equine Veterinary Journal 25:88-89, 1993. Pubmed reference: 8467784.
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.
1991 Bjorneby, J.M., Leach, D.R., Perryman, L.E. :
Persistent Cryptosporidiosis in Horses with Severe Combined Immunodeficiency Infection and Immunity 59:3823-3826, 1991. Pubmed reference: 1894380.
1990 Mair, T.S., Taylor, F.G.R., Harbour, D.A., Pearson, G.R. :
Concurrent Cryptosporidium and Coronavirus Infections in an Arabian Foal with Combined Immunodeficiency Syndrome Veterinary Record 126:127-130, 1990. Pubmed reference: 2156372.
1989 Bue, C.M., Davis, W.C., Magnuson, N.S., Mottironi, V.D., Ochs, H.D., Wyatt, C.R., Perryman, L.E. :
Bone Marrow Transplantation in Horses with Hereditary Severe Combined Immunodeficiency :38-44, 1989.
Kettler, M.K., Weil, M.R., Perryman, L.E. :
Serum Uric Acid Concentrations in Horses Heterozygous for Combined Immunodeficiency American Journal of Veterinary Research 50:2155-2157, 1989. Pubmed reference: 2610446.
1987 Magnuson, N.S., Perryman, L.E., Wyatt, C.R., Mason, P.H., Talmadge, J.E. :
Large granular lymphocytes from SCID horses develop potent cytotoxic activity after treatment with human recombinant interleukin 2. J Immunol 139:61-7, 1987. Pubmed reference: 3108403.
Wyatt, C.R., Magnuson, N.S., Perryman, L.E. :
Defective thymocyte maturation in horses with severe combined immunodeficiency. J Immunol 139:4072-6, 1987. Pubmed reference: 3500980.
1986 Bue, C.M., Davis, W.C., Magnuson, N.S., Mottironi, V.D., Ochs, H.D., Wyatt, C.R., Perryman, L.E. :
Correction of equine severe combined immunodeficiency by bone marrow transplantation. Transplantation 42:14-9, 1986. Pubmed reference: 3523877.
Magnuson, N., Perryman, L., Wyatt, C., Mason, P. :
Purine enzyme activities as markers of lymphocytic differentiation: studies of lymphocytes from horses with severe combined immunodeficiency (SCID). Adv Exp Med Biol 195 Pt B:421-7, 1986. Pubmed reference: 3020915.
1985 Magnuson, N.S., Perryman, L.E. :
Metabolic investigations of horses with severe combined immunodeficiency. Ann N Y Acad Sci 451:87-97, 1985. Pubmed reference: 3878122.
Magnuson, N.S., Perryman, L.E., Suttle, D.P., Robinson, J.L., Mason, P.H., Marta, K.M. :
Metabolic investigations of fibroblasts from horses, Equus caballus, with hereditary severe combined immunodeficiency. Comp Biochem Physiol B 81:781-6, 1985. Pubmed reference: 2992878.
1984 Magnuson, N.S., Perryman, L.E., Wyatt, C.R., Ishizaka, T., Mason, P.H., Namen, A.E., Banks, K.L., Magnuson, J.A. :
Continuous cultivation of equine lymphocytes: evidence for occasional T cell-like maturation events in horses with hereditary severe combined immunodeficiency. J Immunol 133:2518-24, 1984. Pubmed reference: 6207234.
1983 [No authors listed] :
Primary severe combined immunodeficiency (PSCID) of foals. Equine Vet J 15:187-8, 1983. Pubmed reference: 6884308.
Campbell, T.M., Studdert, M.J. :
Reconstitution of primary, severe, combined immunodeficiency in man and horse. Comp Immunol Microbiol Infect Dis 6:101-14, 1983. Pubmed reference: 6189668.
Campbell, T.M., Studdert, M.J., Ellis, W.M., Paton, C.M. :
Attempted reconstitution of a foal with primary severe combined immunodeficiency. Equine Vet J 15:233-7, 1983. Pubmed reference: 6349983.
Magnuson, N.S., Decker, D.M., Perryman, L.E. :
Increased susceptibility of fibroblasts from horses with severe combined immunodeficiency to growth inhibition by 2'-deoxyadenosine. Clin Immunol Immunopathol 29:391-402, 1983. Pubmed reference: 6605826.
Magnuson, N.S., Decker, D.M., Perryman, L.E. :
S-adenosylhomocysteine hydrolase activity in horses, Equus cabalus, with severe combined immunodeficiency. Comp Biochem Physiol B 75:113-7, 1983. Pubmed reference: 6602030.
1982 Perryman, L.E., McGuire, T.C., Torbeck, R.L., Magnuson, N.S. :
Evaluation of fetal liver cell transplantation for immunoreconstitution of horses with severe combined immunodeficiency. Clin Immunol Immunopathol 23:1-9, 1982. Pubmed reference: 7047029.
Yilma, T., Perryman, L.E., McGuire, T.C. :
Deficiency of interferon-gamma but not interferon-beta in Arabian foals with severe combined immunodeficiency. J Immunol 129:931-3, 1982. Pubmed reference: 6180003.
1980 Lew, A.M., Hosking, C.S., Studdert, M.J. :
Immunologic aspects of combined immunodeficiency disease in Arabian foals American Journal of Veterinary Research 41:1161-1166, 1980. Pubmed reference: 7004276.
Perryman, L.E., Torbeck, R.L. :
Combined immunodeficiency of Arabian horses: Confirmation of autosomal recessive mode of inheritance Journal of the American Veterinary Medical Association 176:1250-1251, 1980. Pubmed reference: 7429919.
1979 Perryman, L.E., Buening, G.M., McGuire, T.C., Torbeck, R.L., Poppie, M.J., Sale, G.E. :
Fetal tissue transplantation for immunotherapy of combined immunodeficiency in horses. Clin Immunol Immunopathol 12:238-51, 1979. Pubmed reference: 33778.
Splitter, G.A., Incefy, G.S., Dardenne, M., Iwata, T., McGuire, T.C. :
Arabian horses with severe combined immunodeficiency -- evaluation of functional thymic hormones. Dev Comp Immunol 3:359-63, 1979. Pubmed reference: 478079.
Splitter, G.A., Incefy, G., Iwata, T., McGuire, T.C. :
Evaluation of functional thymic hormones in Arabian horses with severe combined immunodeficiency. Clin Exp Immunol 38:37-44, 1979. Pubmed reference: 230925.
1978 Anon. :
Legal aspects of diagnosing combined immunodeficiency (CID) in Arabian foals American Association of Equine Practitioners Newsletter 2:28-30, 1978.
Perryman, L.E., McGuire, T.C. :
Mixed lymphocyte culture responses in combined immunodeficiency of horses Transplantation 25:50-52, 1978. Pubmed reference: 146281.
Studdert, M.J. :
Primary, severe, combined immunodeficiency disease of Arabian foals Australian Veterinary Journal 54:411-417, 1978. Pubmed reference: 217327.
1977 Poppie, M.J., McGuire, T.C. :
Combined immunodeficiency in foals of Arabian breeding: evaluation of mode of inheritance and estimation of prevalence of affected foals and carrier mares and stallions Journal of the American Veterinary Medical Association 170:31-33, 1977. Pubmed reference: 299745.
1976 McGuire, T.C., Pollara, B., Moore, J.J., Poppie, M.J. :
Evaluation of adenosine deaminase and other purine salvage pathway enzymes in horses with combined immunodeficiency. Infect Immun 13:995-7, 1976. Pubmed reference: 818021.
Poppie, M.J., McGuire, T.C. :
Combined immunodeficiency with failure of colostral immunoglobulins transfer in foals. Vet Rec 99:44-6, 1976. Pubmed reference: 960512.
1975 Banks, K.L., McGuire, T.C. :
Surface receptors on neutrophils and monocytes from immunodeficient and normal horses Immunology 28:581-588, 1975. Pubmed reference: 1126740.
McGuire, T.C., Banks, K.L., Poppie, M.J. :
Combined immunodeficiency in horses: characterization of the lymphocyte defect. Clin Immunol Immunopathol 3:555-66, 1975. Pubmed reference: 803888.
McGuire, T.C., Banks, K.L., Poppie, M.J. :
Animal model of human disease. Combined immunodeficiency (severe), Swiss-type agammaglobulinemia. Am J Pathol 80:551-4, 1975. Pubmed reference: 1163643.
McGuire, T.C., Poppie, M.J., Banks, K.L. :
Hypogammaglobulinemia predisposing to infection in foals. J Am Vet Med Assoc 166:71-5, 1975. Pubmed reference: 162901.
1974 McGuire, T.C., Poppie, M.J., Banks, K.I. :
Combined (B- and T-lymphocyte) immunodeficiency: a fatal genetic disease in Arabian foals Journal of the American Veterinary Medical Association 164:70-76, 1974. Pubmed reference: 4358832.
1973 McGuire, T.C., Poppie, M.J. :
Hypogammaglobulinemia and thymic hypoplasia in horses: a primary combined immunodeficiency disorder. Infect Immun 8:272-7, 1973. Pubmed reference: 4199158.

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