Novel Brown Coat Color (Cocoa) in French Bulldogs Results from a Nonsense Variant in HPS3

Abstract

Brown or chocolate coat color in many mammalian species is frequently due to variants at the B locus or TYRP1 gene. In dogs, five different TYRP1 loss-of-function alleles have been described, which explain the vast majority of dogs with brown coat color. Recently, breeders and genetic testing laboratories identified brown French Bulldogs that did not carry any of the known mutant TYRP1 alleles. We 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 HPS3 gene encodes a protein required for the correct biogenesis of lysosome-related organelles, including melanosomes. Variants in the human HPS3 gene cause Hermansky–Pudlak syndrome 3, which involves a mild form of oculocutaneous albinism and prolonged bleeding time. A variant in the murine Hps3 gene causes brown coat color in the cocoa mouse mutant. We genotyped a cohort of 373 French Bulldogs and found a strong association of the homozygous mutant HPS3 genotype with the brown coat color. The genotype–phenotype association and the comprehensive knowledge on HPS3 function from other species strongly suggests that HPS3:c.2420G>A is the causative variant for the observed brown coat color in French Bulldogs. 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 HPS3co.

Effects of Cocoa Genotypes on Coat Color, Platelets and Coagulation Parameters in French Bulldogs

“…We obtained photographs from 20 French Bulldogs with different coat color genotypes, including five co / co dogs ( Figure 1 , Table S2 ). We confirmed the earlier observation that the eumelanin coat color in adult cocoa dogs ( co / co ) is of a darker brown shade than the eumelanin coat color in TYRP1 deficient dogs ( b / b ) ( Figure 1 A,B) [ 5 ]. However, the data also illustrate an enormous complexity of additive and/or epistatic gene–gene interactions of HPS3 and TYRP1 with other coat color genes.…”

“…In a recent study, the HPS3 :c.2420G>A nonsense variant was found as an additional underlying genetic cause for the brown coat color in French Bulldogs. To distinguish it from the TYRP1 -related phenotype, the resulting color in HPS3 mutant dogs was named cocoa [ 5 ]. TYRP1 -related brown and HPS3 -related cocoa are recessive traits.…”

“…The wildtype alleles at the TYRP1 and HPS3 genes are often abbreviated as B and Co , while the recessive mutant alleles are represented as b and co . The cocoa coat color is slightly darker than the TYRP1 -related brown coat color in French Bulldogs [ 1 , 5 ].…”

Canine coat pigmentation genetics: a review

“…In most instances, however, it is unlikely to be visually discernible from TYRP1 brown. As the HPS3 co variant lightens eumelanin from black to brown (cocoa), it has minimal phenotypic effect on red-based French Bulldogs that predominantly express pheomelanin (Kiener et al 2020).…”

“…In humans, Hermansky-Pudlak syndrome type 3 (HPS3), a form of oculocutaneous albinism associated with clotting deficiencies, mild nystagmus and mildly impaired vision, is a result of HPS3 mutations. In the mouse, the HPS3-mutant cocoa phenotype has also been associated with prolonged bleeding time (Novak et al 1988;Kiener et al 2020). It has not yet been investigated whether the cocoa phenotype in French Bulldogs is associated with ophthalmologic or haematological phenotypes.…”