Categories: Pigmentation phene

Possibly relevant human trait(s) and/or gene(s)s (MIM numbers): 614072 (trait) , 606118 (gene)

Links to MONDO diseases: No links.

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."

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: