OMIA 000595-9615 : Leukocyte adhesion deficiency, type I in Canis lupus familiaris

In other species: cattle , water buffalo , domestic cat

Possibly relevant human trait(s) and/or gene(s) (MIM number): 116920

Mendelian trait/disorder: yes

Mode of inheritance: Autosomal Recessive

Considered a defect: yes

Key variant known: yes

Year key variant first reported: 1999

Cross-species summary: Affected animals die because of extreme susceptibility to infections, caused by an inability of white blood cells (leukocytes) to pass from the blood stream into infected tissue. This inability is due to the lack of a membrane glycoprotein called the leukocyte integrin beta-2 subunit or CD18.

Species-specific name: Canine leukocyte adhesion deficiency

Species-specific description: In canine leukocyte adhesion deficiency (CLAD) of the Irish Setter and the Irish Red and White Setter, leucocytes fail to express CD11/CD18 cell surface integrins due to CD18 deficiency. As these cell surface receptors are necessary for interaction with other cells and the extracellular matrix, affected leucocytes are unable to migrate to sites of infection, participate in phagocytosis, or mount a respiratory burst, which results in recurrent, life-threating infections. Clinical signs include severe, recurrent bacterial skin infections, neonatal omphalophlebitis impaired wound healing, wounds that fail to exhibit purulent exudate, fever, gingivitis, lameness, and enlarged lymph nodes. The mode of inheritance is autosomal recessive.

Edited by Vicki N. Meyers-Wallen, VMD, PhD, Dipl. ACT

Mapping: CFA (31)

Molecular basis: By cloning and sequencing a very likely comparative candidate gene (based on the homologous human and bovine disorder), Kijas et al. (1999) showed that the causative mutation is a missense mutation (Cys36Ser) in the ITGB2 gene, which encodes the integrin beta 2 subunit (CD18). Zimmerman et al. (2013) reported the same mutation in a mixed-breed dog.

Clinical features: Onset of signs is often less than 12 weeks of age, with average age of presentation to the veterinarian at 13.5 weeks. Signs include recurrent infections, neonatal omphalophlebitis, fever, anorexia, lameness, impaired wound healing, severe skin infections, gingivitis, salivation, thickened mandible, enlarged metaphyses of the distal radius, ulna, tibia, and fibula, lameness, enlarged lymph nodes, and low body weight (Creevy et al., 2003a).. Characteristically, wounds fail to exhibit purulent exudate (Kijas et al., 1999) in the face of severe peripheral leukocytosis with a left shift and active granulocytosis in the bone marrow. Untreated dogs often die by 6 months of age. Gene therapy has been successful in reversing clinical signs (Creevy et al., 2003b).

Pathology: While affected dogs mount significant circulating leukocytosis, the leukocytes cannot function normally (Jobling et al., 2003, Trowald-Wigh et al., 2000). Affected animals have decreased levels of leucocyte beta-2 integrins (specifically CD11b/CD18), which are cell surface receptors necessary for interactions with other cells and extracellular matrix. These leukocytes are unable to adhere to cells, migrate through the vasculature to sites of inflammation, participate in phagocytosis of complement-opsonized bacteria, or generate a respiratory burst.

Prevalence: Prevalence of the mutant allele is estimated to be approximately 5% in the US Irish Setter population, and 7.6% in the Australian Irish Setter population (Kijas et al., 1999, Jobling et al., 2003).

Control: There is a PCR-based test available to identify affected, carrier, and noncarrier dogs.

With both Irish Setters and Irish Red and White Setters, carrier to carrier matings are discouraged. As Irish Setters have a large gene pool, so it is recommended to only breed animals that do not carry the mutation. As Irish Red and White Setters have a smaller gene pool, if carriers are bred, they should only be bred to noncarriers, and the offspring should be tested for the mutation.

Genetic testing: There is a PCR-based test available to identify affected, carrier, and noncarrier dogs.

Breeds: Irish Red and White Setter, Irish Setter.

Associated gene:

Symbol Description Species Chr Location OMIA gene details page Other Links
ITGB2 integrin, beta 2 (complement component 3 receptor 3 and 4 subunit) Canis lupus familiaris 31 NC_006613.3 (38547003..38520733) ITGB2 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
Irish Setter Leukocyte adhesion deficiency, type I ITGB2 missense CanFam3.1 31 g.38537012G>C c.107G>C p.C36S 1999 10512685 Variant coordinates obtained from or confirmed by EBI's Some Effect Predictor (VEP) tool

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.
2016 Nasimuzzaman, M., Lynn, D., Ernst, R., Beuerlein, M., Smith, R.H., Shrestha, A., Cross, S., Link, K., Lutzko, C., Nordling, D., Russell, D.W., Larochelle, A., Malik, P., Van der Loo, J.C. :
Production and purification of high-titer foamy virus vector for the treatment of leukocyte adhesion deficiency. Mol Ther Methods Clin Dev 3:16004, 2016. Pubmed reference: 27722179. DOI: 10.1038/mtm.2016.4.
2013 Zimmerman, K.L., McMillan, K., Monroe, W.E., Sponenberg, D.P., Evans, N., Makris, M., Hammond, S.H., Kanevsky Mullarky, I., Boudreaux, M.K. :
Leukocyte adhesion deficiency type I in a mixed-breed dog. J Vet Diagn Invest 25:291-6, 2013. Pubmed reference: 23417082. DOI: 10.1177/1040638713478814.
2011 Bauer, T.R., Olson, E.M., Huo, Y., Tuschong, L.M., Allen, J.M., Li, Y., Burkholder, T.H., Russell, D.W. :
Treatment of canine leukocyte adhesion deficiency by foamy virus vectors expressing CD18 from a PGK promoter. Gene Ther 18:553-9, 2011. Pubmed reference: 21228879. DOI: 10.1038/gt.2010.169.
Hunter, M.J., Tuschong, L.M., Fowler, C.J., Bauer, T.R., Burkholder, T.H., Hickstein, D.D. :
Gene therapy of canine leukocyte adhesion deficiency using lentiviral vectors with human CD11b and CD18 promoters driving canine CD18 expression. Mol Ther 19:113-21, 2011. Pubmed reference: 20859258. DOI: 10.1038/mt.2010.203.
Hunter, M.J., Zhao, H., Tuschong, L.M., Bauer, T.R., Burkholder, T.H., Persons, D.A., Hickstein, D.D. :
Gene therapy for canine leukocyte adhesion deficiency with lentiviral vectors using the murine stem cell virus and human phosphoglycerate kinase promoters. Hum Gene Ther 22:689-96, 2011. Pubmed reference: 21275758. DOI: 10.1089/hum.2010.130.
2010 Nelson, E.J., Tuschong, L.M., Hunter, M.J., Bauer, T.R., Burkholder, T.H., Hickstein, D.D. :
Lentiviral vectors incorporating a human elongation factor 1alpha promoter for the treatment of canine leukocyte adhesion deficiency. Gene Ther 17:672-7, 2010. Pubmed reference: 20164857. DOI: 10.1038/gt.2010.7.
2009 Peranteau, W.H., Heaton, T.E., Gu, Y.C., Volk, S.W., Bauer, T.R., Alcorn, K., Tuschong, L.M., Johnson, M.P., Hickstein, D.D., Flake, A.W. :
Haploidentical in utero hematopoietic cell transplantation improves phenotype and can induce tolerance for postnatal same-donor transplants in the canine leukocyte adhesion deficiency model. Biol Blood Marrow Transplant 15:293-305, 2009. Pubmed reference: 19203720. DOI: 10.1016/j.bbmt.2008.11.034.
2008 Bauer, TR., Allen, JM., Hai, M., Tuschong, LM., Khan, IF., Olson, EM., Adler, RL., Burkholder, TH., Gu, YC., Russell, DW., Hickstein, DD. :
Successful treatment of canine leukocyte adhesion deficiency by foamy virus vectors. Nat Med 14:93-7, 2008. Pubmed reference: 18157138. DOI: 10.1038/nm1695.
Hai, M., Adler, R.L., Bauer, T.R., Tuschong, L.M., Gu, Y.C., Wu, X., Hickstein, D.D. :
Potential genotoxicity from integration sites in CLAD dogs treated successfully with gammaretroviral vector-mediated gene therapy. Gene Ther 15:1067-71, 2008. Pubmed reference: 18369320. DOI: 10.1038/gt.2008.52.
2005 Bauer, TR., Gu, YC., Tuschong, LM., Burkholder, T., Bacher, JD., Starost, MF., Donahue, RE., Sokolic, RA., Hickstein, DD. :
Nonmyeloablative hematopoietic stem cell transplantation corrects the disease phenotype in the canine model of leukocyte adhesion deficiency. Exp Hematol 33:706-12, 2005. Pubmed reference: 15911095. DOI: 10.1016/j.exphem.2005.03.010.
Pfeiffer, I., Brenig, B. :
Frequency of the canine leucocyte adhesion deficiency (CLAD) mutation among Irish red setters in Germany. J Anim Breed Genet 122:140-2, 2005. Pubmed reference: 16130481.
2004 Gu, YC., Bauer, TR., Ackermann, MR., Smith, CW., Kehrli, ME., Starost, MF., Hickstein, DD. :
The genetic immunodeficiency disease, leukocyte adhesion deficiency, in humans, dogs, cattle, and mice. Comp Med 54:363-72, 2004. Pubmed reference: 15357315.
Verfaillie, T., Verdonck, F., Cox, E. :
Simple PCR-based test for the detection of canine leucocyte adhesion deficiency. Vet Rec 154:821-3, 2004. Pubmed reference: 15260444.
2003 Creevy, K.E., Bauer, T.R, Jr., ., Tuschong, L.M., Embree, L.J., Colenda, L., Cogan, K., Starost, M.F., Haskins, M.E., Hickstein, D.D. :
Canine leukocyte adhesion deficiency colony for investigation of novel hematopoietic therapies Veterinary Immunology & Immunopathology 94:11-22, 2003.
Creevy, K.E., Bauer, T.R., Tuschong, L.M., Embree, L.J., Silverstone, A.M., Bacher, J.D., Romines, C., Garnier, J., Thomas, M.L., Colenda, L., Hickstein, D.D. :
Mixed chimeric hematopoietic stem cell transplant reverses the disease phenotype in canine leukocyte adhesion deficiency. Vet Immunol Immunopathol 95:113-21, 2003. Pubmed reference: 12963272.
Jobling, A.I., Ryan, J., Augusteyn, R.C. :
The frequency of the canine leukocyte adhesion deficiency (CLAD) allele within the Irish Setter population of Australia. Aust Vet J 81:763-5, 2003. Pubmed reference: 15080489.
2002 Debenham, S.L., Millington, A., Kijas, J., Andersson, L., Binns, M. :
Canine leucocyte adhesion deficiency in Irish red and white setters Journal of Small Animal Practice 43:74-75, 2002. Pubmed reference: 11873952.
Foureman, P., Whiteley, M., Giger, U. :
Canine leukocyte adhesion deficiency: Presence of the Cys36Ser beta-2 integrin mutation in an affected US Irish Setter cross-breed dog and in US Irish Red and White Setters Journal of Veterinary Internal Medicine 16:518-523, 2002. Pubmed reference: 12322699.
2000 Deptula, W., Czurlowska, M., Medrala, D. :
Inborn deficit of adhesion receptors: a new type of disease in cattle, dogs and humans [Review] [Polish] Medycyna Weterynaryjna 56:150-153, 2000.
Kijas, J.M.H., Juneja, R.K., Gafvert, S., Andersson, L. :
Detection of the causal mutation for canine leukocyte adhesion deficiency (CLAD) using pyrosequencing Animal Genetics 31:326-328, 2000. Pubmed reference: 11105214.
Trowald-Wigh, G., Ekman, S., Hansson, K., Hedhammar, A., af, Segerstad, C.H. :
Clinical, radiological and pathological features of 12 Irish setters with canine leucocyte adhesion deficiency Journal of Small Animal Practice 41:211-217, 2000. Pubmed reference: 10907223.
1999 Kijas, J.M.H., Bauer, T.R., Gafvert, S., Marklund, S., Trowald-Wigh, G., Johannisson, A., Hedhammar, A., Binns, M., Juneja, R.K., Hickstein, D.D., Andersson, L. :
A missense mutation in the beta-2 integrin gene (ITGB2) causes canine leukocyte adhesion deficiency Genomics 61:101-107, 1999. Pubmed reference: 10512685. DOI: 10.1006/geno.1999.5948.
1993 Cox, E., Kuczka, A., Tammen, I., Schwenger, B., Bonte, P., Goddeeris, B. :
Leucocyte Adhesion Deficiency in Cattle and Dogs - A Genetic Defect of the Immune System Vlaams Diergeneeskundig Tijdschrift 62:71-79, 1993.
Trowaldwigh, G., Johannisson, A., Hakansson, L. :
Canine Neutrophil Adhesion Proteins and Fc-Receptors in Healthy Dogs and Dogs with Adhesion Protein Deficiency, as Studied by Flow Cytometry Veterinary Immunology and Immunopathology 38:297-310, 1993. Pubmed reference: 8291207.
1992 Trowaldwigh, G., Hakansson, L., Johannisson, A., Norrgren, L., Segerstad, C.H. :
Leucocyte Adhesion Protein Deficiency in Irish-Setter Dogs Veterinary Immunology and Immunopathology 32:261-280, 1992. Pubmed reference: 1352926.

Edit History


  • Created by Frank Nicholas on 12 Sep 2005
  • Changed by Martha MaloneyHuss on 18 Aug 2011
  • Changed by Frank Nicholas on 12 Dec 2011
  • Changed by Frank Nicholas on 15 Sep 2012
  • Changed by Frank Nicholas on 25 Apr 2013