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A TYR ‐iffic discovery: Identification of a second TYR variant associated with acromelanism in dogs

2024; Wiley; Volume: 56; Issue: 1 Linguagem: Inglês

10.1111/age.13496

1365-2052

Samantha L. Van Buren, Anushka Panjwani, Carrie J. Finno,

Olfactory and Sensory Function Studies

Acromelanism is a form of albinism that results from pigmentation being affected by temperature and causes a 'Himalayan' or 'colorpoint' coat pattern in affected animals. Tyrosinase, encoded by the TYR gene, is an enzyme that is essential for the biosynthesis of melanin (Slominski, 2002). The Himalayan coat color, where the extremities are darker and the torso remains lighter, is due to mutations that result in a temperature-sensitive tyrosinase protein that causes melanin synthesis to occur only in cooler areas of the body. Mutations associated with the Himalayan-type phenotype have been identified in multiple species, including cats (Lyons et al., 2005; Schmidt-Küntzel et al., 2005; Yu et al., 2019), rabbits (Aigner et al., 2000), mice (Beermann et al., 2004; Kwon et al., 1989), mink (Benkel et al., 2009), dogs (Bychkova et al., 2021), baboons (Koga et al., 2020), syrian hamsters (Sakamoto & Hirobe, 2023) and domesticated canaries (Guimarães-Moreira et al., 2024). Some mutations in TYR have been identified as resulting in complete albinism (Imes et al., 2006; Yan et al., 2019). In humans, mutations in this gene that impact pigmentation are classified as Type 1 oculocutaneous albinism (Spritz et al., 1997). Oculocutaneous albinism is a group of inherited disorders characterized by reduced melanin in the skin, hair and eyes. Six of the identified types described in humans are linked to mutations in distinct genes (Yang et al., 2019): TYR (OCA1), OCA2 (OCA2), TYRP1 (OCA3), SLC45A2 (OCA4), SLC24A5 (OCA6) and LRMDA (OCA7). In dogs, mutations affecting pigmentation phenotype have been associated with four of those genes, comprising TYR (Bychkova et al., 2021), OCA2 (Caduff et al., 2017b), TYRP1 (Hrckova Turnova et al., 2017; Schmutz et al., 2002; Van Buren et al., 2021; Wright et al., 2019) and SLC45A2 (Caduff et al., 2017a; Winkler et al., 2014; Wijesena & Schmutz, 2015). Here, we investigated a family of rescue dogs that display a characteristic Himalayan coat color and report a second TYR variant associated with this phenotype in canids. Buccal samples were collected from one non-Himalayan and five Himalayan dogs, with written consent obtained from all owners to participate in the research. These six individuals (CP1, CP2, CP3, CP4, CP5 and CP6) were from two litters (three from each) surrendered to the same shelter approximately 6 months apart with the information that they have the same parents who do not have a Himalayan coat color. The entire TYR coding sequence was sequenced in CP1 and then only exon 1 was subsequently sequenced in the other five individuals, using previously described primer sequences (Bychkova et al., 2021). Genotyping was performed with Sanger sequencing at the UC Berkeley Sanger Sequencing Facility and was visualized with sequencher 5.4.6 software. We identified a novel TYR variant (c.229C>T, p.Arg77Trp) in exon 1 in the homozygous state in the five Himalayan dogs. This variant was predicted to be deleterious to protein function by the PredictSNP consensus classifier with 87% confidence and has been named the 'ch2' variant. All five Himalayan dogs were ch2/ch2 and the one non-Himalayan dog was homozygous wild type, as shown in Figure 1. Interestingly, the ch2 variant is in the same codon as the first identified Himalayan variant in dogs (c.230G>A, p.Arg77Gln) (Bychkova et al., 2021). A commercial coat color test was conducted through the UC Davis Veterinary Genetics Laboratory to evaluate the background coat color of the individuals. The genetic results are presented in Table S1. To assess kinship between the six individuals and confirm suspected relatedness, a short tandem repeat panel was performed by the UC Davis Veterinary Genetics Laboratory. A matrix was constructed between each pair of individuals using 53 autosomal short tandem repeats, and the proportion of shared alleles was assessed, similar to previous reports (Sosiawan et al., 2019; Yudianto et al., 2022). Based on Mendelian inheritance and assuming non-linkage, full siblings are expected to exhibit 25% two-allele sharing, 50% one-allele sharing and 25% no-allele sharing (Moffatt et al., 1994). In this analysis, each potential pair exhibited 9.4–26.4% two-allele sharing, 64.2–90.6% one-allele sharing and 0–13.2% no allele sharing (Table S2), suggesting some deviation from the 25–50–25% expectation but still indicating a degree of relatedness. The increased allele sharing observed may also indicate inbreeding effects, which can shift allele sharing ratios away from Mendelian predictions (Kamarudin et al., 2020). We suspect the ch2 variant to be de novo to this family line, as it was not identified in any of the 668 domestic dogs and 54 wild canids present in the The Dog Biomedical Variant Database Consortium (Plassais et al., 2019). Given that both parents are presumed to be wild type, we predict this variant to be recessive, similar to other Himalayan mutations in other species as well as in the previously identified dog mutation affecting the same codon (Bychkova et al., 2021). Samantha L. Van Buren: Conceptualization; investigation; writing – original draft; methodology; validation; visualization; writing – review and editing; software; formal analysis; data curation. Anushka Panjwani: Validation; writing – review and editing. Carrie J. Finno: Writing – review and editing; investigation; project administration; supervision; resources. This work was supported by Jastro-Shields Scholarship from the College of Agriculture and Environmental Sciences, University of California Davis. Thanks go to the Oconee Humane Society and to the dog owners for providing information, samples, and photos. The authors declare no conflicts of interest. All relevant data are available in the manuscript text and supporting information. Table S1. Table S2. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.