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A large deletion in the GP9 gene in Cocker Spaniel dogs with Bernard-Soulier syndrome.
PLoS One 2019; 14(9):e0220625Plos

Abstract

Inherited bleeding disorders including abnormalities of platelet number and function rarely occur in a variety of dog breeds, but are probably underdiagnosed. Genetically characterized canine forms of platelet disorders provide valuable large animal models for understanding similar platelet disorders in people. Breed-specific disease associated genetic variants in only eight different genes are known to cause intrinsic platelet disorders in dogs. However, the causative genetic variant in many dog breeds has until now remained unknown. Four cases of a mild to severe bleeding disorder in Cocker Spaniel dogs are herein presented. The affected dogs showed a platelet adhesion defect characterized by macrothrombocytopenia with variable platelet counts resembling human Bernard-Soulier syndrome (BSS). Furthermore, the lack of functional GPIb-IX-V was demonstrated by immunocytochemistry. Whole genome sequencing of one affected dog and visual inspection of the candidate genes identified a deletion in the glycoprotein IX platelet (GP9) gene. The GP9 gene encodes a subunit of a platelet surface membrane glycoprotein complex; this functions as a receptor for von Willebrand factor, which initiates the maintenance of hemostasis after injury. Variants in human GP9 are associated with Bernard-Soulier syndrome, type C. The deletion spanned 2460 bp, and included a significant part of the single coding exon of the canine GP9 gene on dog chromosome 20. The variant results in a frameshift and premature stop codon which is predicted to truncate almost two-thirds of the encoded protein. PCR-based genotyping confirmed recessive inheritance. The homozygous variant genotype seen in affected dogs did not occur in 98 control Cocker Spaniels. Thus, it was concluded that the structural variant identified in the GP9 gene was most likely causative for the BSS-phenotype in the dogs examined. These findings provide the first large animal GP9 model for this group of inherited platelet disorders and greatly facilitate the diagnosis and identification of affected and/or normal carriers in Cocker Spaniels.

Authors+Show Affiliations

Department of Veterinary Medical Sciences, University of Bologna, Bologna, Italy.Genefast, Forlì, Italy.Department of Veterinary Medical Sciences, University of Bologna, Bologna, Italy.Department of Veterinary Medical Sciences, University of Bologna, Bologna, Italy.Department of Veterinary Medical Sciences, University of Bologna, Bologna, Italy.Genomia, Plzen, Czech Republic.Institute of Genetics, Vetsuisse Faculty, University of Bern, Bern, Switzerland.Institute of Genetics, Vetsuisse Faculty, University of Bern, Bern, Switzerland.Institute of Genetics, Vetsuisse Faculty, University of Bern, Bern, Switzerland.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

31484196

Citation

Gentilini, Fabio, et al. "A Large Deletion in the GP9 Gene in Cocker Spaniel Dogs With Bernard-Soulier Syndrome." PloS One, vol. 14, no. 9, 2019, pp. e0220625.
Gentilini F, Turba ME, Giancola F, et al. A large deletion in the GP9 gene in Cocker Spaniel dogs with Bernard-Soulier syndrome. PLoS ONE. 2019;14(9):e0220625.
Gentilini, F., Turba, M. E., Giancola, F., Chiocchetti, R., Bernardini, C., Dajbychova, M., ... Drögemüller, C. (2019). A large deletion in the GP9 gene in Cocker Spaniel dogs with Bernard-Soulier syndrome. PloS One, 14(9), pp. e0220625. doi:10.1371/journal.pone.0220625.
Gentilini F, et al. A Large Deletion in the GP9 Gene in Cocker Spaniel Dogs With Bernard-Soulier Syndrome. PLoS ONE. 2019;14(9):e0220625. PubMed PMID: 31484196.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - A large deletion in the GP9 gene in Cocker Spaniel dogs with Bernard-Soulier syndrome. AU - Gentilini,Fabio, AU - Turba,Maria Elena, AU - Giancola,Fiorella, AU - Chiocchetti,Roberto, AU - Bernardini,Chiara, AU - Dajbychova,Markéta, AU - Jagannathan,Vidhya, AU - Drögemüller,Michaela, AU - Drögemüller,Cord, Y1 - 2019/09/04/ PY - 2019/03/12/received PY - 2019/07/20/accepted PY - 2019/9/5/entrez PY - 2019/9/5/pubmed PY - 2019/9/5/medline SP - e0220625 EP - e0220625 JF - PloS one JO - PLoS ONE VL - 14 IS - 9 N2 - Inherited bleeding disorders including abnormalities of platelet number and function rarely occur in a variety of dog breeds, but are probably underdiagnosed. Genetically characterized canine forms of platelet disorders provide valuable large animal models for understanding similar platelet disorders in people. Breed-specific disease associated genetic variants in only eight different genes are known to cause intrinsic platelet disorders in dogs. However, the causative genetic variant in many dog breeds has until now remained unknown. Four cases of a mild to severe bleeding disorder in Cocker Spaniel dogs are herein presented. The affected dogs showed a platelet adhesion defect characterized by macrothrombocytopenia with variable platelet counts resembling human Bernard-Soulier syndrome (BSS). Furthermore, the lack of functional GPIb-IX-V was demonstrated by immunocytochemistry. Whole genome sequencing of one affected dog and visual inspection of the candidate genes identified a deletion in the glycoprotein IX platelet (GP9) gene. The GP9 gene encodes a subunit of a platelet surface membrane glycoprotein complex; this functions as a receptor for von Willebrand factor, which initiates the maintenance of hemostasis after injury. Variants in human GP9 are associated with Bernard-Soulier syndrome, type C. The deletion spanned 2460 bp, and included a significant part of the single coding exon of the canine GP9 gene on dog chromosome 20. The variant results in a frameshift and premature stop codon which is predicted to truncate almost two-thirds of the encoded protein. PCR-based genotyping confirmed recessive inheritance. The homozygous variant genotype seen in affected dogs did not occur in 98 control Cocker Spaniels. Thus, it was concluded that the structural variant identified in the GP9 gene was most likely causative for the BSS-phenotype in the dogs examined. These findings provide the first large animal GP9 model for this group of inherited platelet disorders and greatly facilitate the diagnosis and identification of affected and/or normal carriers in Cocker Spaniels. SN - 1932-6203 UR - https://www.unboundmedicine.com/medline/citation/31484196/A_large_deletion_in_the_GP9_gene_in_Cocker_Spaniel_dogs_with_Bernard-Soulier_syndrome L2 - http://dx.plos.org/10.1371/journal.pone.0220625 DB - PRIME DP - Unbound Medicine ER -