CLAD in Irish Setters

Immunological syndrome CLAD (canine leukocyte adhesion deficiency) is a fatal disease affecting Irish Setters. The disease is very similar to LAD in humans or BLAD in cattle. Manifestation of CLAD in Irish Setters was first described by Renshaw et al 1975. A few years later, autosomal recessive inheritance of CLAD was recognized (Renshaw and Davis, 1979). Giger et al. 1987 found out lack of CD18 molecule expression in animals with frequent infections. Finally, Trowald-Wigh et al. in 1992 described and confirmed the existence of CLAD disease Irish Setters (red and white).

All types of immunological syndrome (CLAD, BLAD, LAD) are caused by congenital disorder of ß2-leukocyte integrin (molecule is known as CD18). Integrins are heterodimeric glycoproteins composed of α and ß particles. Integrins are located on the surface of white blood cells. Integrins help to leukocytes incorporating to inflammatory tissues. Intrgrins intermediate cell-cell and cell-substratum adhesion reactions in the body. If a part of integrin molecule is destroyed, there is a lack of immune response to the presence of infection in the body. Affected body is unable to effectively prevent the attack of bacteria.

The genetic nature of CLAD was found out by a team of Swedish, American and British scientists (Kijas et al. 1999). CLAD is caused by single mutation G→C in position 107, exon 3, ß2-integrin gene (ITGB2). This mutation causes Cysteine to Serine substitution in position 36 of ß2-integrin protein molecule. This Cysteine is normally involved in disulfide bond. Because of the mutation, disulfide bond cannot be formed. That leads to protein conformation and function disruption. Cys36Ser mutation was not found in other dog breeds except Irish Setters. The frequency of heterozygotes in the Irish Setter's population in Australia is 7,6% (Jobling et al. 2003), which is less than in Europe, where the allelic frequency is 0,11. Statistical data from the U.S. are not known.

CLAD is autosomal recessive inherited disease. That means the disease affects dogs with P/P (positive / positive) genotype only. The dogs with P/N (positive / negative) genotype are clinically without any symptom. They are genetically considered carriers of the disease (heterozygotes). In offspring of two heterozygous animals following genotype distribution can be expected: 25 % N/N (healthy non-carriers), 25 % P/P (affected), and 50 % N/P (healthy carriers). Because of high risk of producing affected offspring, mating of two N/P animals (carriers) can not be recommended. Molecular genetic test is based on direct DNA sequencing and allows detecting of presence or absence of the mutations and determining the carriers.

Clinically, CLAD is manifested by repeatedly returning infections, bad wounds curing, immunosuppression, skin and marrow infections. Affected puppies are usually smaller and slower developing. From the beginning, they suffer from various infections (umbilical cord, tonsillitis and teeth ridge) and they are more vulnerable. Later, marrow inflammation appears; the affected animal has movement difficulties and finally is not able to stand up. Affected individuals may not show at the same time all symptoms described above. Individuals with CLAD disease usually die very soon.

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References:
Renshaw, H. W., Chatburn, C., Bryan, G. M., Bartsch, R. C., Davis, W. C. (1975). Canine Granulocytopathy syndrome: Neutrophil dysfunction in a dog with recurrent infections. J. Am. Vet. Med. Assoc. 166: 443-447.
Renshaw, H. W., Davis, W. C. (1979). Canine granulocytopathy syndrome: An inherited disorder of leukocyte function. Am. J. Pathol. 95: 731-743.
Trowald-Wigh, G., Håkansson, L., Johannison, A., Norrgren, L.,Hård af Segerstad, C. (1992). Leucocyte adhesion protein deficiency in Irish setter dogs. Vet. Immunol. Immunopathol. 32: 261-380.
Giger, U., Boxer, L. A., Simpson, P. J., Lucchesi, B. R., Todd, R. F., III (1987). Deficiency of leukocyte surface glycoproteins Mo1, LFA-1, and Leu M5 in a dog with recurrent bacterial infections: An animal model. Blood 69: 1622-1630.
J. M. H. Kijas, T. R. Bauer, Jr., S. Gäfvert, S. Marklund, Trowald-Wigh, A. Johannisson, Å. Hedhammar, M. Binns, R. K. Juneja, D. D. Hickstein, L. Andersson: A Missense Mutation in the b-2 Integrin Gene (ITGB2) Causes Canine Leukocyte Adhesion Deficiency, Genomics 61, 101-107 (1999)
Jobling AI, Ryan J, Augusteyn RC.: The frequency of the canine leukocyte adhesion deficiency (CLAD) allele within the Irish Setter population of Australia. Aust Vet J. 2003 Dec;81(12):763-5.