[pstinard]

Here is one more scholarly article about the association between dilute (blue) coat color and Color Dilution Alopecia: Welle et al. 2009. MLPH Genotype—Melanin Phenotype Correlation in Dilute Dogs. Journal of Heredity 100:S75-S79.

The article concludes that dilute (blue) coat color is necessary, but not sufficient for the development of Color Dilution Alopecia. In other words, not all Blue Yorkies will develop the baldness and skin disorders, but it does dispose them towards developing them. Here are a few quotes from the article:

Coat color dilution in dogs is a specific pigmentation phenotype caused by a defective transport of melanosomes leading to large clumps of pigment. It is inherited as a Mendelian autosomal recessive trait and may be accompanied by hair loss, the so-called color dilution alopecia (CDA), or black hair follicular dysplasia (BHFD). We previously identified the noncoding c.-22G>A transition in the melanophilin gene (MLPH) as a candidate causative mutation for the dilute phenotype. We have now extended our study and genotyped 935 dogs from 20 breeds segregating for dilute coat color. The dilute-associated A allele segregates in many different breeds suggesting an old mutation event. We also investigated skin biopsies of dogs suspected of having either CDA or BHFD, and our data clearly indicate that the dilute mutation is required but not sufficient to develop clinical signs of the disease. The risk to develop CDA/BHFD seems to be breed specific. Interestingly, 22 out of 29 dogs with clinical signs of CDA/BHFD have clumped melanin in the epidermis, the follicular epithelium, and the hair shafts, whereas in dilute dogs without clinical disease, clumped melanin is only found in the follicular epithelium and the hair shafts but not in the epidermis.

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Dogs with dilute coat color are known in many breeds. In dilute dogs, the eumelanin- or phaeomelanin-pigmented skin appears paler and is denoted breed specific, foe example, blue, gray, Isabella, fawn, silver, or pale brown (Schmutz and Berryere 2007). As the change in phaeomelanin is not as dramatic as the eumelanin dilution, red-colored dogs are sometimes difficult to detect as dilute. Coat color dilution (d) is inherited as a Mendelian autosomal recessive trait in various dog breeds (Schmutz et al. 1998). Coat color dilution is characterized by a defective transport of melanosomes within follicular melanocytes, which is mainly regulated by 3 interacting proteins (MLPH, MYO5A, and RAB27A) (Barral and Seabra 2004; Hume et al. 2006; Hume et al. 2007). The dilution phenotype occurs in different mammalian species, and causative mutations within the melanophilin gene (MLPH) have been identified in, for example, human, mouse, and cat (Matesic et al. 2001; Ménasché et al. 2003; Ishida et al. 2006). In a previous study, we applied a candidate gene approach and showed that dilute dogs from different breeds share a common approximately 10-kb haplotype block at the 5’ end of the MLPH gene. Within this shared haplotype block, a noncoding single nucleotide polymorphism (SNP) at the splice donor of exon 1 (c.-22G>A) represents a candidate causal mutation for coat color dilution in 7 dog breeds. The MLPH mRNA expression in skin biopsies of dilute beagles carrying the mutant A allele was lower than in beagles carrying the wild-type G allele (Philipp, Hamann, et al. 2005; Philipp, Quignon, et al. 2005; Drögemüller et al. 2007).

Coat color dilution has been described as a predisposing risk factor for certain forms of hair loss in dogs (Mecklenburg 2006). Both, color dilution alopecia (CDA; also known as color mutant alopecia) and black hair follicular dysplasia (BHFD), also known as dark hair follicular dysplasia (Selmanowitz et al. 1972), are primarily noninflammatory forms of hair loss that occur in various dog breeds. CDA is associated with a dilute coat color (Laukner 1998), and hair loss is usually most severe on the dorsal trunk. BHFD occurs in the pigmented coat areas of spotted dogs, for example, in the Large Munsterlander (Schmutz et al. 1998). Some authors consider both diseases to be etiologically identical (Carlotti 1990). BHFD is usually clinically noted within the first weeks of age and comprises fracture of hair shafts in dark coated regions, resulting in partial alopecia and scaling. First clinical signs of CDA are usually noticed between 3 and 12 months of age, rarely later in life, and lesions are usually slowly progressive with age. Affected dogs are prone to secondary pyoderma. With regard to histopathology, CDA is identical to BHFD (Gross et al. 2005, Mecklenburg 2006). Affected skin reveals large clumps of melanin within melanocytes in the hair matrix, the outer root sheath of the hair follicle, and within the hair shaft. The affected hair shafts frequently break within the hair canal resulting in a more or less distorted follicular infundibulum, which is often plugged with keratin, fragmented hairs, and large irregular clumps of melanin. The amount of clumped melanin is variable among breeds and individuals and so is the expressivity of clinical disease (Hargis et al. 1991; Mecklenburg 2006). Some dogs with exactly the same histological findings in the hair follicles have no signs of alopecia, whereas others may have complete hair loss. About 25% of the gray/blue dogs of both sexes show clinical symptoms, whereas the others do not develop alopecia. In addition, not all dogs that have symptoms develop them at a similar age of onset or with similar severity (Schmutz and Berryere 2007). Obviously, some dog breeds, for example, the Large Munsterlander (von Bomhard et al. 2006), develop more easily clinical symptoms than other breeds, such as the Weimaraner, where if symptoms occur at all, they are less pronounced (Laffort-Dassot et al. 2002; Schmutz and Berryere 2007). Unfortunately, no comprehensive study on the breed distribution of CDA or BHFD has been published. A possible influence of other genes besides MLPH influencing the expressivity of clinical disease is under debate, and recently the canine RAB27A gene was analyzed as possible candidate gene. However, no indication for associated nucleotide polymorphisms in the coding region of RAB27A was found (Schmutz and Berryere 2007).

We now conducted an extensive screening experiment to survey in which breeds the MLPH c.-22G>A mutation occurs and for which of the various coat colors in different breeds this mutation might be causative. We also investigated the MLPH genotypes and the histopathological findings in skin biopsies of 45 dogs suspected of having either CDA or BHFD in order to develop an improved phenotypic classification of CDA and a better understanding for additional disease-promoting factors apart from coat color dilution.

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In conclusion, we found perfect association of the MLPH c.-22G>A SNP with dilute coat color in more than 900 dogs supporting the hypothesis that this polymorphism is indeed the causative mutation. The wide breed distribution of the mutant MLPH c.-22G>A allele suggests an old mutation event. Although our data clearly indicate that the MLPH mutation increases the risk for CDA/BHFD, there seem to be additional modifying factors. A characteristic feature of most CDA/BHFD–affected dogs is the presence of clumped melanin in the epidermis. In some breeds, such as the pinscher breeds and the Rhodesian ridgebacks, the reported coat quality of dilute dogs ranges from normal to severely CDA affected. Therefore, these breeds offer the chance to search for modifier genes, which influence the risk of developing CDA/BHFD in dogs with dilute coat color.