In other species: domestic ferret , domestic cat , taurine cattle , sheep , rabbit , American mink

Categories: Pigmentation phene

Links to possible relevant human trait(s) and/or gene(s) in OMIM: 609227 (trait) , 606526 (gene)

Links to relevant human diseases in MONDO:

• MONDO:0012220: Griscelli syndrome type 3

Mendelian trait/disorder: yes

Mode of inheritance: Autosomal recessive

Disease-related: yes

Key variant known: yes

Year key variant first reported: 2007

Cross-species summary: FN acknowledges invaluable feedback from Cord Drögemüller that has led to the name of this phene being changed from "Coat colour, diluted" to "Coat colour, dilution, MLPH-related". At the same time, a new phene "Coat colour, dilution, generic" was created.

Species-specific name: Colour mutant alopecia; Color dilution alopecia; Colour dilution alopecia; Black Hair Follicular Dysplasia; Blue Doberman Syndrome

Species-specific symbol: d, CDA, BHFD

Mapping: Philipp et al. (2005) mapped a very likely comparative candidate gene to canine chromosome CFA25q24. The candidate gene was inferred from the leaden mouse mutant with a variant in the Mlph gene. Three different mouse mutants with similar pigmentation phenotypes exist (ashen - Rab27a gene; dilute - Myo5a gene; leaden - Mlph gene). Leaden mice only show the characteristic pigment dilution. Ashen mice have diluted pogmentation and a severe immunological phenotype. Dilute mice have diluted pigmentation and a severe neurological phenotype.

Molecular basis: By cloning and sequencing a very likely comparative candidate gene (based on the homologous phenotype in humans and mice), namely MLPH, Drögemüller et al. (2007) identified a causal mutation as an "an A/G SNP located at the last nucleotide of the untranslated exon 1 (c.-22G>A)" which "affects a conserved nucleotide of the splice donor recognition motif". As a result of the "reduction of splicing efficiency", the authors reported that "the mutant A-allele is predicted to reduce splicing efficiency 8-fold". Bauer et al. (2018) "investigated dilute coloured Chow Chows whose coat colour could not be explained by their genotype at the previously known MLPH: c.–22G>A variant [allele d^1]. Whole genome sequencing of such a dilute Chow Chow revealed another variant in the MLPH gene: MLPH:c.705G>C [allele d^2] . . . Although relatively rare overall, this d2 allele is segregating in at least three dog breeds, Chow Chows, Sloughis and Thai Ridgebacks". Van Buren et al. (2020) reported a third variant "(c.667_668insC) (d^3), which leads to a frameshift and premature stop codon (p.His223Profs*41)". The altered pigmentation is caused by defective transport of melanosomes along microtubule and actin filaments (Barral and Seabra, 2004). Deficiency of MLPH leads to large aggregates of melanosomes, the so-called macromelanosomes. The export of melanosomes from melanocytes into e.g. growing hair shafts is impaired.

Clinical features: In dogs, MLPH-related color dilution predisposes to a skin disease termed color dilution alopecia (CDA). The health problems appear to be specific to dogs. In other mammalian species, loss-of-function of the MLPH gene exclusively results in coat color dilution, without any known health problems (e.g. cats, mice, rats). A fraction of the dogs with MLPH-related dilute coat color develop hair loss or alopecia (Welle et al., 2009). This disease is termed color dilution alopecia (CDA). The CDA phenotype is highly variable in severity. Mildly affected dogs will show some hair loss, but are otherwise healthy and do not require therapy. In more severe forms, the hair loss can be extensive and a generalized inflammation of the skin may develop (folliculitis). This causes puritus and/or pain to the dogs and will require treatment with antibiotics. The skin infections in severely affected dogs will be recurring and require life-long treament. The pigment dilution leads to large melanin aggregates, the so-called macromelanosomes. Incorporation of large macromelanosomes into growing hair shafts reduces their mechanical stability and makes them susceptible to hair shaft breaks, which manifest as clinically visible hypotrichosis or alopecia. The proximal parts of broken hair shafts may irritate the infundibulum and this may cause the folliculitis. There are clear breed differences in the susceptibility to CDA. In some breeds, dilute-coloured dogs rarely or never develop CDA (e.g. Weimaraners). In other breeds, most or even all dilute-coloured dogs will develop CDA. It is therefore not recommended to introgress dilute alleles into new breeds. A deterrent example are the Labrador Retrievers with dilute coat colors (silver, charcoal, champagne) that were bred by introgression of Weimaraners into Labrador Retrievers. While the dilute Weimaraners are rarely or never affected with CDA, dilute colored Labrador Retrievers are very prone to develop a severe form of CDA. In dilute-colored dogs with white spotting, only the pigmented skin areas will be affected by CDA, while the unpigmented skin and hair remains normal. This phenotype has occasionally been termed black hair follicular dysplasia (BHFD), e.g. in Large Münsterlanders (von Bomhard et al., 2006). It is suggested to consistently apply the term CDA to all forms of alopecia that are caused by MLPH-related coat color dilution and pigment aggregation. The term BHFD has been used in different contexts and may also have been used for genetically distinct forms of alopecia (e.g. Bohnhorst et al., 2001).

Pathology: von Bomhard et al. (2006) investigated a litter of Large Münsterländer cross-bred dogs, of which four puppies were affected with CDA (BHFD). "...Affected dogs were born with silvery grey hair, a consequence of melanin clumping in the hair shafts. Hair bulb melanocytes were densely pigmented, and contained abundant stage IV melanosomes but adjacent matrix keratinocytes lacked melanosomes. Melanin clumping was not prominent in epidermal melanocytes in the haired skin but occurred in the foot pads. Follicular changes progressed from bulbar clumping, clumping in the isthmus/infundibulum and finally to dysplastic hair shafts. Alopecia developed progressively in pigmented areas. ..." and "...In all affected dogs, epidermal melanocytes were heavily pigmented with perinuclear accumulation of pigment. Cellular processes were rarely identifiable. The surrounding keratinocytes were sparsely pigmented." Welle et al. (2009) noted that "... 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."

Prevalence: Van Buren et al. (2020): "The d^3 allele is found at low frequency in multiple dog breeds, as well as in wolves, wolf-dog hybrids, and indigenous dogs.The d3 allele was found in a wide spectrum of breeds and other canids, minimally including the Hungarian pumi, Hungarian mudi, Chihuahua, Pekingese, Italian greyhound, Shih Tzu, Tibetan mastiff, Yorkshire terrier, and Shetland sheepdog, as well as indigenous dogs, wolves, and wolf-dog hybrids. The wolf-dog hybrids in this study that carry the d3 variant have recent ancestry behind them, including wolf, Alaskan Malamute, German shepherd dog, Siberian husky, and collie. The presence of the d3 variant in village dogs and wolves may indicate that this variant represents an ancient mutation, persisting at a low frequency across some breeds, while being lost in others. However, given that this variant is a single nucleotide insertion in an 8 bp poly C stretch, the possibility that d3 is identical by state, at least in some breeds, must be considered."

Genetic testing: Van Buren et al. (2020): "As this newly identified c.667_668insC d3 variant does not resolve all MLPH genotype/phenotype inconsistencies, additional variants are likely. This fact must be taken under consideration when performing genetic testing and counseling."

Breeds: American Staffordshire Terrier (Dog) (VBO_0200055), Beagle (Dog) (VBO_0200131), Belgian Shepherd Dog, Malinois (Dog) (VBO_0200147), Chihuahua (Dog) (VBO_0200338), Chow Chow (Dog) (VBO_0200361), Dachshund (Dog) (VBO_0200406), Doberman Pinscher (Dog) (VBO_0200442), German Pinscher (Dog) (VBO_0201454), German Shepherd Dog (Dog) (VBO_0200577), Gordon Setter (Dog) (VBO_0200613), Huntaway (Dog) (VBO_0200683), Italian Greyhound (Dog) (VBO_0200713), Jack Russell Terrier (Dog) (VBO_0200724), Large Munsterlander (Dog) (VBO_0200816), Miniature Pinscher (Dog) (VBO_0200893), Mudi (Dog) (VBO_0200921), Pekingese (Dog) (VBO_0200994), Puli (Dog) (VBO_0201102), Rhodesian Ridgeback (Dog) (VBO_0201135), Shetland Sheepdog (Dog) (VBO_0201217), Shih Tzu (Dog) (VBO_0201223), Sloughi (Dog) (VBO_0201242), Thai Ridgeback (Dog) (VBO_0201348), Tibetan Mastiff (Dog) (VBO_0201351), Yorkshire Terrier (Dog) (VBO_0201448).
Breeds in which the phene has been documented. (If a likely causal variant has been documented for the phene, see the variant table breeds in which the variant has been reported).

Associated gene: