In other species: Japanese medaka , western gorilla , taurine cattle

Categories: Pigmentation phene

Possibly relevant human trait(s) and/or gene(s)s (MIM numbers): 606574 (trait) , 227240 (trait) , 606202 (gene)

Links to MONDO diseases:

• MONDO:0011683: oculocutaneous albinism type 4

Mendelian trait/disorder: yes

Mode of inheritance: Autosomal recessive

Considered a defect: yes

Key variant known: yes

Year key variant first reported: 2014

Species-specific name: White Doberman Pinscher

Species-specific symbol: WDP

History: As reported by Winkler et al. (2014), "In 1976, a female Doberman pinscher with novel “white” coat-coloration was born and registered with the American Kennel Club. The uniqueness of the light coat-color prompted breeders to utilize line breeding to maintain the phenotype, resulting in an extensive pedigree in which all living white Doberman pinschers (WDPs) are traceable to this initial white female."

Inheritance: As reported by Winkler et al. (2014), "A research study conducted by the DPCA [Doberman Pincher Club of America] concluded an autosomal recessive mode of inheritance (http://dpca.org/BreedEd/index.php/articles/44-history/381-albinism-science)".

Mapping: Based on the very strong phenotypic resemblance between the white phenotype of Doberman Pinschers and oculocutaneous albinism (OCA) in humans, Winkler et al. (2014) obtained flanking markers from the canine genome assembly for the canine orthologues of four of the genes involved in OCD in humans, namely tyrosinase (TYR) for OCA1, P-gene for OCA2, tyrosinase-related protein 1 (TYRP1) for OCA3, and solute carrier family, member 2 (SLC45A2) for OCA4. An exclusion analysis involving 20 white and 20 standard Doberman Pinchers eliminated all but the last candidate gene.

Molecular basis: Sequencing of the candidate gene in one white and one standard Doberman Pincher "revealed a 4,081 base pair deletion resulting in loss of the terminus of exon seven of SLC45A2 (chr4[ratio]77,062,968–77,067,051)" (g.27141_31223del (CanFam2)) as a highly likely causative mutation (Winkler et al., 2014). As also reported by Winkler et al. (2014), "This mutation is predicted to cause the last 50 amino acids of exon 7 to be replaced by 191 new amino acids before an in-frame stop codon is found, as predicted from the canine reference genome (CanFam2.0) . . . . This deletion also removes the poly-A addition signal (AATAAA), and the next predicted polyadenylation signal for the mutant chromosome is 6,106 bp downstream from the new stop codon." Wijesena and Schmutz (2015): c.1478G>A; p.G493D in exon 7 in a female albino Lhasa Apso and in "an albino Pekingese, 2 albino Pomeranians, and an albino mixed breed dog that was small and long haired" Caduff et al. (2017) reported a likely causal variant in Bullmastiffs: "a single base deletion in exon 6 of the SLC45A2 gene (NM_001037947.1:c.1287delC) . . . This deletion is predicted to result in an early premature stop codon. It was confirmed by Sanger sequencing and perfectly co-segregated with the phenotype in the available family members. We genotyped 174 unrelated dogs from diverse breeds, all of which were homozygous wildtype."

Genetic engineering: Unknown
Have human generated variants been created, e.g. through genetic engineering and gene editing

Clinical features: Dogs with oculocutaneous albinism type IV have white (cream) coat coloration, blue eyes (iris), pink nose and lips, hypopigmented adnexal structures (eyelid margins, nictitating membrane margins, and cilia), and hypopigmented retinal pigment epithelium and choroid (Winkler et al., 2014). Dogs may also present with photophobia and vision defects (Winkler et al., 2014). Additionally, exposure of the hypopigmented skin to ultraviolet radiation may result in cutaneous melanocytic neoplasms and/or ocular masses (Caduff et al., 2017; Winkler et al., 2014). IT thanks DVM student Arpan Mann, who provided the basis of this contribution in May 2023.

Breeds: Bull Mastiff (Dog) (VBO_0200253), Doberman Pinscher (Dog) (VBO_0200442), Lhasa Apso (Dog) (VBO_0200824), Pekingese (Dog) (VBO_0200994), Pomeranian (Dog) (VBO_0201043).
Breeds in which the phene has been documented. For breeds in which a likely causal variant has been documented, see the variant table below

Associated gene: