In other species: domestic cat , taurine cattle , indicine cattle (zebu) , water buffalo

Categories: Immune system phene

Links to possible relevant human trait(s) and/or gene(s) in OMIM: 116920 (trait) , 600065 (gene)

Links to relevant human diseases in MONDO:

• MONDO:0007293: leukocyte adhesion deficiency 1

Mendelian trait/disorder: yes

Mode of inheritance: Autosomal recessive

Disease-related: 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 (Dog) (VBO_0200700), Irish Setter (Dog) (VBO_0200702), Mixed Breed (Dog) (VBO_0200902).
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: