OMIA 002275-9615 : Coat colour, cocoa in Canis lupus familiaris
Laukner et al. (2021) "studied the genotype-phenotype correlation regarding coat color in HPS3 mutant dogs that carried various combinations of mutant alleles at other coat color genes. Different combinations of HPS3, MLPH and TYRP1 genotypes resulted in subtly different shades of brown coat colors."Molecular basis: Kiener et al. (2020) "sequenced the genome of a TYRP1+/+ brown French Bulldog and compared the data to 655 other canine genomes. A search for private variants revealed a nonsense variant in HPS3, c.2420G>A or p.(Trp807*). The brown dog was homozygous for the mutant allele at this variant." The authors genotyped a cohort of 373 French Bulldogs and found a strong association of the homozygous mutant HPS3 genotype with the brown coat color.
The HPS3 gene encodes a subunit of a protein complex named "Biogenesis of Lysosome-related Organelles Complex-2 (BLOC-2)". This protein complex controls the sorting and transport of newly synthesized integral membrane proteins from early endosomes to both lysosomes and lysosome-related organelles, such as melanosomes and platelet-dense granules. Loss of function variants in HPS3 therefore may result in a syndromic phenotype that was initially recognized in humans with Hermansky-Pudlak syndrome 3. This phenotype is characterized by pigment dilution, mildly reduced visual acuity and a mild bleeding disorder due to the absence of platelet-dense bodies.
"Based on the comprehensive knowledge on HPS3 function together with the observed genotype–phenotype association" Kiener et al. 2020 concluded that "HPS3:c.2420G>A is very likely the causative genetic variant for the brown coat color in the investigated French Bulldogs".Clinical features: HPS3 deficient (cocoa) coloured dogs are born brown. Their colour darkens with age and they become slightly darker than TYRP1-deficient (chocolate) dogs as adults (Kiener et al. 2020). So far, it has not been investigated whether cocoa coloured dogs have any bleeding disorder or visual impairments, similar to what has been observed in human patients with Hermansky-Pudlak syndrome 3. Pathology: Laukner et al. (2021): "As HPS3 variants in humans cause the Hermansky-Pudlak syndrome type 3, which in addition to oculocutaneous albinism is characterized by a storage pool deficiency leading to bleeding tendency, we also investigated the phenotypic consequences of the HPS3 variant in French Bulldogs on hematological parameters. HPS3 mutant dogs had a significantly lowered platelet dense granules abundance. However, no increased bleeding tendencies in daily routine were reported by dog owners." Breed: French Bulldog. Associated gene:
|Symbol||Description||Species||Chr||Location||OMIA gene details page||Other Links|
|HPS3||Hermansky-Pudlak syndrome 3||Canis lupus familiaris||23||NC_051827.1 (44566353..44606057)||HPS3||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|
|1215||French Bulldog||Cocoa||HPS3||HPS3^co||nonsense (stop-gain)||Naturally occurring variant||CanFam3.1||23||g.43969695G>A||c.2420G>A||p.(T807*)||XM_542830.6:c.2420G>A; XP_542830.3:p.(Trp807*)||2020||32526956|
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.
|2021||Brancalion, L., Haase, B., Wade, C.M. :|
|Canine coat pigmentation genetics: a review. Anim Genet :, 2021. Pubmed reference: 34751460. DOI: 10.1111/age.13154.|
|Laukner, A., Truchet, L., Manukjan, G., Schulze, H., Langbein-Detsch, I., Mueller, E., Leeb, T., Kehl, A. :|
|Effects of Cocoa genotypes on coat color, platelets and coagulation parameters in French bulldogs. Genes (Basel) 12:, 2021. Pubmed reference: 34356108. DOI: 10.3390/genes12071092.|
|2020||Kiener, S., Kehl, A., Loechel, R., Langbein-Detsch, I., Müller, E., Bannasch, D., Jagannathan, V., Leeb, T. :|
|Novel brown coat color (cocoa) in French bulldogs results from a nonsense variant in HPS3. Genes (Basel) 11:, 2020. Pubmed reference: 32526956. DOI: 10.3390/genes11060636.|
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