OCA2 splice site variant in German Spitz dogs with oculocutaneous albinism

Caduff, Madleina; Bauer, Anina; Jagannathan, Vidhya; Leeb, Tosso

doi:10.1371/journal.pone.0185944

Cited by 14 publications

(27 citation statements)

References 21 publications

(29 reference statements)

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“…In dogs, the wildtype allele B leading to black coat color is dominant, whereas the recessive brown phenotype is the result of any combination of two mutant b alleles [15]. A splice site variant in the OCA2 gene was reported in three German Spitz siblings with a light brown coat color in combination with blue eyes and mild photophobia [19].…”

Section: Introductionmentioning

confidence: 99%

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

Kiener

Kehl

Loechel³

et al. 2020

Genes

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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.

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Section: Introductionmentioning

confidence: 99%

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

Kiener

Kehl

Loechel³

et al. 2020

Genes

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“…The mechanisms of OCA pathogenesis have been reported in rodents, dogs, and water buffaloes [28][29][30][31]. However, these OCA animal models present the major limitation of the absence of a foveal structure similar to that of the human retina.…”

Section: Introductionmentioning

confidence: 99%

Nonhuman Primate Model of Oculocutaneous Albinism with TYR and OCA2 Mutations

Yang

et al. 2020

Research

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Human visual acuity is anatomically determined by the retinal fovea. The ontogenetic development of the fovea can be seriously hindered by oculocutaneous albinism (OCA), which is characterized by a disorder of melanin synthesis. Although people of all ethnic backgrounds can be affected, no efficient treatments for OCA have been developed thus far, due partly to the lack of effective animal models. Rhesus macaques are genetically homologous to humans and, most importantly, exhibit structures of the macula and fovea that are similar to those of humans; thus, rhesus macaques present special advantages in the modeling and study of human macular and foveal diseases. In this study, we identified rhesus macaque models with clinical characteristics consistent with those of OCA patients according to observations of ocular behavior, fundus examination, and optical coherence tomography. Genomic sequencing revealed a biallelic p.L312I mutation in TYR and a homozygous p.S788L mutation in OCA2, both of which were further confirmed to affect melanin biosynthesis via in vitro assays. These rhesus macaque models of OCA will be useful animal resources for studying foveal development and for preclinical trials of new therapies for OCA.

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“…White coat color is a common color in dogs caused by at least two underlying distinct genetic mechanisms: the absence of melanocytes in the skin/hair or the absence of pigment in the melanocytes or hairs. In dogs, true albinism is rare and is due to SLC45A2 or OCA2 mutations [1,2,3,4]. The absence of melanocytes in the skin, also called piebaldism or leucism, is a variable phenotype ranging from white spots to more extreme white patterns, resulting in almost-white coat color with few pigmented areas.…”

Section: Introductionmentioning

confidence: 99%

Identification of a Missense Variant in MFSD12 Involved in Dilution of Phaeomelanin Leading to White or Cream Coat Color in Dogs

Hédan

Cadieu

Botherel

et al. 2019

Genes

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White coat color in mammals has been selected several times during the domestication process. Numerous dog breeds are fixed for one form of white coat color that involves darkly pigmented skin. The genetic basis of this color, due to the absence of pigment in the hairs, was suggested to correspond to extreme dilution of the phaeomelanin, by both the expression of only phaeomelanin (locus E) and its extreme dilution (locus I). To go further, we performed genome-wide association studies (GWAS) using a multiple breed approach. The first GWAS, using 34 white dogs and 128 non-white dogs, including White Shepherds, Poodles, Cotons de Tulear and Bichons allowed us to identify two significantly associated loci on the locus E and a novel locus on chromosome 20. A second GWAS using 15 other breeds presenting extreme phaeomelanin dilution confirmed the position of locus I on the chromosome 20 (position 55 Mb pcorrected = 6 × 10−13). Using whole-genome sequencing, we identified a missense variant in the first exon of MFSD12, a gene recently identified to be involved in human, mouse and horse pigmentation. We confirmed the role of this variant in phaeomelanin dilution of numerous canine breeds, and the conserved role of MFSD12 in mammalian pigmentation.

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OCA2 splice site variant in German Spitz dogs with oculocutaneous albinism

Cited by 14 publications

References 21 publications

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

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

Nonhuman Primate Model of Oculocutaneous Albinism with TYR and OCA2 Mutations

Identification of a Missense Variant in MFSD12 Involved in Dilution of Phaeomelanin Leading to White or Cream Coat Color in Dogs

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