OMIA:000031-9615 : Coat colour, dilution, MLPH-related in Canis lupus familiaris
Categories: Pigmentation phene
Links to MONDO diseases:
Mendelian trait/disorder: yes
Mode of inheritance: Autosomal recessive
Considered a defect: 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).
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."
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, Beagle, Chihuahua, Chow Chow, Dachshund, Doberman Pinscher, German Pinscher, German Shepherd Dog, Gordon Setter, Hungarian mudi, Hungarian Puli, Italian Greyhound, Jack Russell Terrier, Large Munsterlander, Miniature Pinscher, New Zealand Huntaway Dog, Pekingese, Rhodesian Ridgeback, Shetland Sheepdog, Shih-Tzu, Sloughi, Thai Ridgeback, Tibetan Mastiff, Yorkshire Terrier.
|Symbol||Description||Species||Chr||Location||OMIA gene details page||Other Links|
|MLPH||melanophilin||Canis lupus familiaris||25||NC_051829.1 (48506862..48555710)||MLPH||Homologene, Ensembl , NCBI gene|
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WARNING! Inclusion of a variant in this table does not automatically mean that it should be used for DNA testing. Anyone contemplating the use of any of these variants for DNA testing should examine critically the relevant evidence (especially in breeds other than the breed in which the variant was first described). If it is decided to proceed, the location and orientation of the variant sequence should be checked very carefully.
Since October 2021, OMIA includes a semiautomated lift-over pipeline to facilitate updates of genomic positions to a recent reference genome position. These changes to genomic positions are not always reflected in the ‘acknowledgements’ or ‘verbal description’ fields in this table.
|OMIA Variant ID||Breed(s)||Variant Phenotype||Gene||Allele||Type of Variant||Source of Genetic Variant||Reference Sequence||Chr.||g. or m.||c. or n.||p.||Verbal Description||EVA ID||Inferred EVA rsID||Year Published||PubMed ID(s)||Acknowledgements|
|360||American Staffordshire Terrier Beagle Doberman Pinscher German Pinscher Large Munsterlander Miniature Pinscher Rhodesian Ridgeback||Dilute||MLPH||d^1||splicing||Naturally occurring variant||CanFam3.1||25||g.48121642G>A||c.-22G>A||2007||17519392||Variant coordinates obtained from or confirmed by EBI's Variant Effect Predictor (VEP) tool|
|1216||Chihuahua Hungarian mudi Hungarian pumi Italian Greyhound Pekingese Shetland Sheepdog Shih-Tzu Tibetan Mastiff Yorkshire Terrier||Dilute||MLPH||d^3||insertion, small (<=20)||Naturally occurring variant||CanFam3.1||25||g.48150749_50insC||c.667_668insC||p.(H223Pfs*41)||"(NM_001103219.2: c.667_668insC or chr25: g.48150749_50insC" (van Buren et al. (2020)||2020||32531980|
|948||Chow Chow Sloughi Thai Ridgeback||Dilute||MLPH||d^2||missense||Naturally occurring variant||CanFam3.1||25||g.48150787G>C||c.705G>C||p.(Q235H)||2018||29349785|
Cite this entry
Note: the references are listed in reverse chronological order (from the most recent year to the earliest year), and alphabetically by first author within a year.
|2023||Arizmendi, A., Rudd Garces, G., Crespi, J.A., Olivera, L.H., Barrientos, L.S., Peral García, P., Giovambattista, G. :|
|Analysis of Doberman Pinscher and Toy Poodle samples with targeted next-generation sequencing. Gene 853:147069, 2023. Pubmed reference: 36427679 . DOI: 10.1016/j.gene.2022.147069.|
|Meadows, J.R.S., Kidd, J.M., Wang, G.D., Parker, H.G., Schall, P.Z., Bianchi, M., Christmas, M.J., Bougiouri, K., Buckley, R.M., Hitte, C., Nguyen, A.K., Wang, C., Jagannathan, V., Niskanen, J.E., Frantz, L.A.F., Arumilli, M., Hundi, S., Lindblad-Toh, K., Ginja, C., Agustina, K.K., André, C., Boyko, A.R., Davis, B.W., Drögemüller, M., Feng, X.Y., Gkagkavouzis, K., Iliopoulos, G., Harris, A.C., Hytönen, M.K., Kalthoff, D.C., Liu, Y.H., Lymberakis, P., Poulakakis, N., Pires, A.E., Racimo, F., Ramos-Almodovar, F., Savolainen, P., Venetsani, S., Tammen, I., Triantafyllidis, A., vonHoldt, B., Wayne, R.K., Larson, G., Nicholas, F.W., Lohi, H., Leeb, T., Zhang, Y.P., Ostrander, E.A. :|
|Genome sequencing of 2000 canids by the Dog10K consortium advances the understanding of demography, genome function and architecture. Genome Biol 24:187, 2023. Pubmed reference: 37582787 . DOI: 10.1186/s13059-023-03023-7.|
|2022||[No authors listed] :|
|Canine coat pigmentation genetics: a review. Anim Genet 53:474-475, 2022. Pubmed reference: 35510419 . DOI: 10.1111/age.13185.|
|Brancalion, L., Haase, B., Wade, C.M. :|
|Canine coat pigmentation genetics: a review. Anim Genet 53:33-34, 2022. Pubmed reference: 34751460 . DOI: 10.1111/age.13154.|
|2021||Caramalac, S.M., Caramalac, S.M., Babo-Terra, V.J., Ramos, C.A.N., Palumbo, M.I.P. :|
|PCR-RFLP molecular confirmation of color dilution alopecia in dogs in Brazil. J Vet Diagn Invest 33:984-6, 2021. Pubmed reference: 34088257 . DOI: 10.1177/10406387211022309.|
|2020||Van Buren, S.L., Minor, K.M., Grahn, R.A., Mickelson, J.R., Grahn, J.C., Malvick, J., Colangelo, J.R., Mueller, E., Kuehnlein, P., Kehl, A. :|
|A third MLPH variant causing coat color dilution in dogs. Genes (Basel) 11:, 2020. Pubmed reference: 32531980 . DOI: 10.3390/genes11060639.|
|2018||Bauer, A., Kehl, A., Jagannathan, V., Leeb, T. :|
|A novel MLPH variant in dogs with coat colour dilution. Anim Genet 49:94-97, 2018. Pubmed reference: 29349785 . DOI: 10.1111/age.12632.|
|2009||Munday, JS., French, AF., McKerchar, GR. :|
|Black-hair follicular dysplasia in a New Zealand Huntaway Dog. N Z Vet J 57:170-2, 2009. Pubmed reference: 19521467 . DOI: 10.1080/00480169.2009.36898.|
|Perego, R., Proverbio, D., Roccabianca, P., Spada, E. :|
|Color dilution alopecia in a blue Doberman pinscher crossbreed. Can Vet J 50:511-4, 2009. Pubmed reference: 19436637 .|
|Welle, M., Philipp, U., Rüfenacht, S., Roosje, P., Scharfenstein, M., Schuetz, E., Brenig, B., Linek, M., Mecklenburg, L., Grest, P., Drögemüller, M., Haase, B., Leeb, T., Drögemüller, C. :|
|MLPH genotype melanin phenotype correlation in dilute dogs. Journal of Heredity 100:S75–S79, 2009.|
|2007||Drögemüller, C., Philipp, U., Haase, B., Günzel-Apel, A.R., Leeb, T. :|
|A noncoding melanophilin gene (MLPH) SNP at the splice donor of exon 1 represents a candidate causal mutation for coat color dilution in dogs. J Hered 98:468-73, 2007. Pubmed reference: 17519392 . DOI: 10.1093/jhered/esm021.|
|2006||von Bomhard, W., Mauldin, EA., Schmutz, SM., Leeb, T., Casal, ML. :|
|Black hair follicular dysplasia in Large Münsterländer dogs: clinical, histological and ultrastructural features. Vet Dermatol 17:182-8, 2006. Pubmed reference: 16674733 . DOI: 10.1111/j.1365-3164.2006.00517.x.|
|2005||Kim, JH., Kang, KI., Sohn, HJ., Woo, GH., Jean, YH., Hwang, EK. :|
|Color-dilution alopecia in dogs. J Vet Sci 6:259-61, 2005. Pubmed reference: 16131833 .|
|Philipp, U., Quignon, P., Scott, A., Andre, C., Breen, M., Leeb, T. :|
|Chromosomal assignment of the canine melanophilin gene (MLPH): A candidate gene for coat color dilution in pinschers. J Hered 96:774-6, 2005. Pubmed reference: 15958794 . DOI: 10.1093/jhered/esi079.|
|Philipp, U., Hamann, H., Mecklenburg, L., Nishino, S., Mignot, E., Gunzel-Apel, AR., Schmutz, SM., Leeb, T. :|
|Polymorphisms within the canine MLPH gene are associated with dilute coat color in dogs. BMC Genet 6:34, 2005. Pubmed reference: 15960853 . DOI: 10.1186/1471-2156-6-34.|
|2004||Barral, D.C., Seabra, M.C. :|
|The melanosome as a model to study organelle motility in mammals. Pigment Cell Res 17:111-8, 2004. Pubmed reference: 15016299 . DOI: 10.1111/j.1600-0749.2004.00138.x.|
|2002||Laffort-Dassot, C., Beco, L., Carlotti, D.N. :|
|Follicular dysplasia in five Weimaraners Veterinary Dermatology 13:253-260, 2002. Pubmed reference: 12358609 .|
|2001||Bohnhorst, J.O., Hanssen, I., Moen, T. :|
|Antinuclear antibodies (ANA) in Gordon setters with symmetrical lupoid onychodystrophy and black hair follicular dysplasia Acta Veterinaria Scandinavica 42:323-329, 2001. Pubmed reference: 11887392 .|
|1999||Castellano, M.C., Idiart, J.R. :|
|Colour dilution alopecia in a German Shepherd dog Canine Practice 24:6-7, 1999.|
|Osthold, W., Beck, J. :|
|Black Hair Follicular Dysplasie in a mixed-breed dog [German] Kleintierpraxis 44:685-+, 1999.|
|1998||Rothstein, E., Scott, D.W., Miller, W.H., Bagladi, M.S. :|
|A retrospective study of dysplastic hair follicles and abnormal melanization in dogs with follicular dysplasia syndromes or endocrine skin disease Veterinary Dermatology 9:235-241, 1998.|
|Schmutz, SM., Moker, JS., Clark, EG., Shewfelt, R. :|
|Black hair follicular dysplasia, an autosomal recessive condition in dogs. Can Vet J 39:644-6, 1998. Pubmed reference: 9789677 .|
|1997||Madewell, B.R., Ihrke, P.J., Griffey, S.M. :|
|Multiple skin tumours in a Doberman Pinscher with colour dilution alopecia Veterinary Dermatology 8:59-61, 1997.|
|1996||Beco, L., Fontaine, J., Gross, T.L., Charlier, G. :|
|Colour dilution alopecia in seven Dachshunds - a clinical study and the hereditary, microscopical and ultrastructural aspect of the disease Veterinary Dermatology 7:91-97, 1996.|
|Knottenbelt, C.M., Knottenbelt, M.K. :|
|Black hair follicular dysplasia in a tricolour Jack Russell terrier Veterinary Record 138:475-476, 1996. Pubmed reference: 8735542 .|
|1995||Delmage, D.A. :|
|Black hair follicular dysplasia Veterinary Record 136:79-80, 1995. Pubmed reference: 7725619 .|
|Lewis, C.J. :|
|Black hair follicular dysplasia in UK bred Salukis Veterinary Record 137:294-295, 1995. Pubmed reference: 8533225 .|
|Lowenstein, C. :|
|Color mutant alopecia in a yorkshire terrier [German] Kleintierpraxis 40:781 ff., 1995.|
|Roperto, F., Cerundolo, R., Restucci, B., Vincensi, M.R., Decaprariis, D., Devico, G., Maiolino, P. :|
|Colour dilution alopecia (cda) in ten yorkshire terriers Veterinary Dermatology 6:171-178, 1995.|
|1993||Finnie, J.W., Tham, V.L. :|
|Colour mutant alopecia in a Kelpie X Border Collie dog Australian Veterinary Journal 70:388-389, 1993. Pubmed reference: 8257319 .|
|1977||Selmanowitz, VJ., Markofsky, J., Orentreich, N. :|
|Black-hair follicular dysplasia in dogs. J Am Vet Med Assoc 171:1079-81, 1977. Pubmed reference: 591423 .|
|1972||Selmanowitz, VJ., Kramer, KM., Orentreich, N. :|
|Canine hereditary black hair follicular dysplasia. J Hered 63:43-4, 1972. Pubmed reference: 5019544 .|
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