OMIA:002433-9615 : Thrombopathia, RASGRP2-related in Canis lupus familiaris (dog)
In other species: taurine cattle
Categories: Haematopoietic system phene
Links to MONDO diseases:
Mendelian trait/disorder: yes
Mode of inheritance: Autosomal recessive
Considered a defect: yes
Key variant known: yes
Year key variant first reported: 2007
Species-specific name: CalDAG-GEFI thrombopathia; CalDAG-GEFI platelet disorder
Species-specific description: Boudreaux et al. (2007) reported likely causal variants in Calcium-Diacylglycerol Guanine Nucleotide Exchange Factor I (CalDAG-GEFI). Based on NCBI information the gene name was listed as RASGRP1 gene in OMIA. A recent BLAST search of the published data identified that the correct gene name is RASGRP2. Information from OMIA 001003-9615 'Thrombopathia in Canis lupus familiaris' was moved to this entry and variant table information was updated accordingly [22/01/2022].
Molecular basis: Boudreaux et al. (2007) reported this disorder in three breeds being due to three different mutations in the RASGRP2 gene that encodes Calcium-Diacylglycerol Guanine Nucleotide Exchange Factor I (CalDAG-GEFI): Eskimo Spitz dogs have frameshift mutation (452-453insA), Bassett Hounds have a three-base deletion (509-511delTCT), and Landseers have a nonsense mutation (982C>T).
Have human generated variants been created, e.g. through genetic engineering and gene editing
Clinical features: Variants in the gene that encodes CalDAG-GEFI cause decreased fibrinogen receptor activation (Cortese et al., 2020) and severely impaired or absent platelet aggregation response to adenosine diphosphate, collagen, and platelet activating factor (Boudreaux et al., 2007). There is also a delayed but full response to thrombin (Boudreaux, 2012). The clot retraction assay is normal (Boudreaux, 2012), but the kinetics are impaired – the time to full aggregation is prolonged to 4-6min compared to 3min in unaffected dogs (Cortese et al., 2020).
Clinically, affected dogs experience epistaxis, gingival bleeding and petechiation on mucous membranes and skin, and prolonged bleeding time (Boudreaux et al., 2007). Platelet counts and coagulation screening tests will have normal results (Boudreaux, 2012). Some affected Basset Hounds may present with weakness and rear limb paralysis secondary to spinal cord haemorrhage (Boudreaux, 2012).
IT thanks DVM student Jovial Zheng, who provided the basis of this contribution in May 2023.
Breeds in which the phene has been documented. For breeds in which a likely causal variant has been documented, see the variant table below
|Symbol||Description||Species||Chr||Location||OMIA gene details page||Other Links|
|RASGRP2||RAS guanyl releasing protein 2 (calcium and DAG-regulated)||Canis lupus familiaris||18||NC_051822.1 (53453534..53467923)||RASGRP2||Homologene, Ensembl , NCBI gene|
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WARNING! Inclusion of a variant in this table does not automatically mean that it should be used for DNA testing. Anyone contemplating the use of any of these variants for DNA testing should examine critically the relevant evidence (especially in breeds other than the breed in which the variant was first described). If it is decided to proceed, the location and orientation of the variant sequence should be checked very carefully.
Since October 2021, OMIA includes a semiautomated lift-over pipeline to facilitate updates of genomic positions to a recent reference genome position. These changes to genomic positions are not always reflected in the ‘acknowledgements’ or ‘verbal description’ fields in this table.
|OMIA Variant ID||Breed(s)||Variant Phenotype||Gene||Allele||Type of Variant||Source of Genetic Variant||Reference Sequence||Chr.||g. or m.||c. or n.||p.||Verbal Description||EVA ID||Inferred EVA rsID||Year Published||PubMed ID(s)||Acknowledgements|
|585||Eskimo Spitz||Thrombopathia||RASGRP2||duplication||Naturally occurring variant||CanFam3.1||18||g.52417256dup||c.452dup||p.(D151Efs)||XM_849829.5; XP_854922.1; published as c.452-453insA||2007||17656327|
|477||Basset Hound||Thrombopathia||RASGRP2||deletion, small (<=20)||Naturally occurring variant||CanFam3.1||18||g.52417313_52417315del||c.509_511del||p.(F170del)||XM_849829.5; XP_854922.1||2007||17656327|
|285||Landseer||Thrombopathia||RASGRP2||nonsense (stop-gain)||Naturally occurring variant||CanFam3.1||18||g.52419245C>T||c.982C>T||p.(R328*)||XM_849829.5; XP_854922.1||2007||17656327|
Cite this entry
Note: the references are listed in reverse chronological order (from the most recent year to the earliest year), and alphabetically by first author within a year.
|2020||Cortese, L., Christopherson, P.W., Pelagalli, A. :|
|Platelet function and therapeutic applications in dogs: current status and future prospects. Animals (Basel) 10, 2020. Pubmed reference: 31991713. DOI: 10.3390/ani10020201.|
|2012||Boudreaux, M.K. :|
|Inherited platelet disorders. J Vet Emerg Crit Care (San Antonio) 22:30-41, 2012. Pubmed reference: 22316339. DOI: 10.1111/j.1476-4431.2011.00702.x.|
|2008||Boudreaux, MK. :|
|Characteristics, diagnosis, and treatment of inherited platelet disorders in mammals. J Am Vet Med Assoc 233:1251-9, 1190, 2008. Pubmed reference: 18922051. DOI: 10.2460/javma.233.8.1251.|
|2007||Boudreaux, MK., Catalfamo, JL., Klok, M. :|
|Calcium-diacylglycerol guanine nucleotide exchange factor I gene mutations associated with loss of function in canine platelets. Transl Res 150:81-92, 2007. Pubmed reference: 17656327. DOI: 10.1016/j.trsl.2007.03.006.|
|1994||Boudreaux, M.K., Crager, C., Dillon, A.R., Stanz, K., Toiviokinnucan, M. :|
|Identification of an intrinsic platelet function defect in Spitz dogs. Journal of Veterinary Internal Medicine 8:93-98, 1994. Pubmed reference: 8046682.|
|1989||Patterson, W.R., Estry, D.W., Schwartz, K.A., Borchert, R.D., Bell, T.G. :|
|Absent platelet aggregation with normal fibrinogen binding in Basset Hound hereditary thrombopathy. Thrombosis and Haemostasis 62:1011-1015, 1989. Pubmed reference: 2512673.|
|1985||Patterson, W.R., Padgett, G.A., Bell, T.G. :|
|Abnormal release of storage pool adenine nucleotides from platelets of dogs affected with basset hound hereditary thrombopathy. Thromb Res 37:61-71, 1985. Pubmed reference: 3983903.|
|1979||Johnstone, IB., Lotz, F. :|
|An inherited platelet function defect in Basset hounds. Can Vet J 20:211-5, 1979. Pubmed reference: 509382.|
- Created by Imke Tammen2 on 22 Jan 2022
- Changed by Imke Tammen2 on 14 Jun 2023