A missense mutation in the β-2 integrin gene (ITGB2) causes canine leukocyte adhesion deficiency

被引:68
作者
Kijas, JMH
Bauer, TR
Gäfvert, S
Marklund, S
Trowald-Wigh, G
Johannisson, A
Hedhammar, Å
Binns, M
Juneja, RK
Hickstein, DD
Andersson, L
机构
[1] Swedish Univ Agr Sci, Uppsala Biomed Ctr, Dept Anim Breeding & Genet, S-75124 Uppsala, Sweden
[2] Swedish Univ Agr Sci, Dept Small Anim Med & Surg, S-75124 Uppsala, Sweden
[3] Swedish Univ Agr Sci, Dept Pathol, S-75124 Uppsala, Sweden
[4] Univ Washington, Sch Med, VA Puget Sound Hlth Care Syst 151, Seattle, WA 98108 USA
[5] Anim Hlth Trust, Kentford CB8 7UU, Suffolk, England
关键词
D O I
10.1006/geno.1999.5948
中图分类号
Q81 [生物工程学(生物技术)]; Q93 [微生物学];
学科分类号
071005 ; 0836 ; 090102 ; 100705 ;
摘要
Canine leukocyte adhesion deficiency (CLAD) is a fatal immunodeficiency disease found in Irish setters. The clinical manifestations of CLAD are very similar to LAD in humans and BLAD in cattle, which are both caused by mutations in ITGB2 encoding the leukocyte integrin beta-2 subunit (CD18). Sequence analysis of the ITGB2 coding sequence from a CLAD dog and a healthy control revealed a single missense mutation, Cys36Ser. This cysteine residue is conserved among all beta integrins, and the mutation most likely disrupts a disulfide bond. The mutation showed a complete association with CLAD in Irish setters and was not found in a sample of dogs from other breeds. The causative nature of this mutation was confirmed by transduction experiments using retroviral vectors and human LAD EBV B-cells. The normal canine CD18 formed heterodimers with the human CD11 subunit, whereas gene transfer of the mutant CD18 resulted in very low levels of CD11/CD18 expression. The identification of the causative mutation for CLAD now makes it possible to identify carrier animals with a simple diagnostic DNA test, and it forms the basis for using CLAD as a large animal model for the development and evaluation of clinical treatments for human LAD. (C) 1999 Academic Press.
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页码:101 / 107
页数:7
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