A mutation in the kindlin-3 gene associated with combined leukocyte and platelet dysfunction
Abstract number: PP-MO-754
Boudreaux1 M.K., Wardrop2 J., Kiklevich3 V., Felsburg4 P.
11Pathobiology, Auburn University, Auburn 22Clinical Pathology, Washington State University, Pullman 33San Antonio Veterinary Referral Specialists, Referral Practice, San Antonio 44Department of Clinical Studies-PHL, University of Pennsylvania, Philadelphia, USA
How-to-cite Boudreaux MK, Wardrop J, Kiklevich V, Felsburg P. A mutation in the kindlin-3 gene associated with combined leukocyte and platelet dysfunction. Journal of Thrombosis and Haemostasis 2009; Volume 7, Supplement 2: Abstract PP-MO-754
Introduction: Kindlin-3 is solely expressed in hematopoietic cells and is important in mediating integrin activation via beta tail interactions. Mutations in the gene encoding kindlin-3 were recently documented in people with prolonged bleeding, leukocytosis without pus formation, and persistent infections. We evaluated a German Shepherd dog with similar clinical presentation including bleeding and persistently elevated leukocyte counts.
Methods: DNA was isolated from whole blood and subjected to PCR using primers specific for genes encoding kindlin-3, calcium diacylglycerol guanine nucleotide exchange factor I (CalDAG-GEFI), CD41, and CD61. PCR products were directly sequenced and evaluated in the affected dog and compared to several controls. Flow cytometry and clot retraction assays were also performed.
Results: Clot retraction was markedly impaired. Flow cytometry indicated that CD41 and CD61 were present on platelets and CD11a, CD11b, CD11c and CD18 were present on leukocytes. Mutations were not detected in the genes encoding CalDAG-GEFI, CD41, or CD61. A 12 base pair insertion was found in the gene encoding kindlin-3. This mutation is predicted to result in insertion of amino acids RRLP within the kindlin-3 pleckstrin-homology domain located within the F2 FERM subdomain. The mutation likely results in marked impairment of protein function, particularly with respect to mediating integrin activation.
Conclusions: This is the first documented mutation in the gene encoding kindlin-3 in a large animal model. The clinical presentation mirrors that reported in people and further underscores the importance of kindlin-3 in mediating integrin activation in platelets and leukocytes.
References: Kuijpers TW et al.: LAD1/variant syndrome is caused by mutations in FERMT3. Blood, DOI 10.1182/blood-2008-10-182154.
Disclosure of interest: none declared.
To cite this abstract use the following format:
Journal of Thrombosis and Haemostasis 2007; Volume 5, Supplement 2: abstract number
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