OMIA 002275-9615 : Coat colour, cocoa in Canis lupus familiaris

Possibly relevant human trait(s) and/or gene(s) (MIM number): 614072

Mendelian trait/disorder: yes

Mode of inheritance: Autosomal Recessive

Considered a defect: unknown

Key variant known: yes

Year key variant first reported: 2020

Cross-species summary: Loss of function variants in the HPS3 gene encoding "HPS3 biogenesis of lysosomal organelles complex 2 subunit 1" may lead to a phenotype characterized by pigment dilution, (mildly) impaired visual acuity, nystagmus, and a (mild) bleeding disorder.

History: Kiener et al. (2020): "In order to clearly distinguish HPS3-related from the TYRP1-related brown coat color, and in line with the murine nomenclature, we propose to designate this dog phenotype as "cocoa", and the mutant allele as HPS3^co."

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.

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

Variants

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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.

Breed(s) Variant Phenotype Gene Allele Type of Variant Reference Sequence Chr. g. or m. c. or n. p. Verbal Description EVA ID Year Published PubMed ID(s) Acknowledgements
French Bulldog Cocoa HPS3 HPS3^co nonsense (stop-gain) CanFam3.1 23 g43969695G>A c.2420G>A p.(Trp807*) XM_542830.6:c.2420G>A; XP_542830.3:p.(Trp807*) 2020 32526956

Reference


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 <i>HPS3</i>. Genes (Basel) 11:, 2020. Pubmed reference: 32526956. DOI: 10.3390/genes11060636.

Edit History


  • Created by Frank Nicholas on 14 Jun 2020
  • Changed by Frank Nicholas on 14 Jun 2020
  • Changed by Tosso Leeb on 16 Jun 2020
  • Changed by Tosso Leeb on 17 Jun 2020