In other species: dog , domestic ferret , domestic cat , 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

Single-gene trait/disorder: yes

Mode of inheritance: Autosomal recessive

Disease-related: no

Key variant known: yes

Year key variant first reported: 2015

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: Cool gray; Larson Blue

Species-specific description: In a reversal of the normal sequence of discovery, Li et al. (2016) discovered this phenotype AFTER identifying the causal mutation, by noticing that all Belgian Blue cattle with a particular mutation (MLPH: c.87_96del; p.Glu32Aspfs*1), which inactivates MLPH, have an expected dilution phenotype which the authors called "cool gray".

History: Dikmen et al. (2017) reported "a previously undescribed coat color phenotype in Holstein cattle. Larson Blue Holsteins, located on a dairy in south Florida, exhibit a coloration pattern that is similar to that of black and white or red and white Holsteins except that, instead of being black or red, darker regions of the body vary in color from gray to taupe. The Larson Blue phenotype was readily apparent in young calves."

Molecular basis: As reported by Li et al. (2016) [published online in 2015], "In the course of a reverse genetic screen in the Belgian Blue cattle breed, we uncovered a 10-bp deletion (c.87_96del) in the first coding exon of the melanophilin gene (MLPH), which introduces a premature stop codon (p.Glu32Aspfs*1) in the same exon, truncating 94% of the protein." Belgian Blue cattle homozygous for this mutant (and with the appropriate genotype at the epistatic KIT locus) all exhibited a dilution coat colour phenotype (as expected with a mutation that inactivates MLPH), which the authors called "cool gray". Having shown that the Larson Blue "phenotype is not due to inheritance of known mutations causing coat color variation in cattle, including dominant red, Telstar, silver color dilutor, or Dun color", Dikmen et al. (2017) whole-genome sequenced two Larson Blue cows and identified "Three variants with moderate effects on the melanophilin (MLPH) gene were identified in 2 Larson blue cows" but noted that "tools for prediction of the simultaneous effect of 3 missense mutations on the MLPH protein are not available, so additional research is needed to confirm the effect of these AA changes on MLPH function. It is also not known whether the variants identified in MLPH exist in wild-type cows in the Larson herd."

Prevalence: Li et al. (2016) reported a 5% frequency of the p.Glu32Aspfs*1 allele in Belgian Blue cattle.

Breed: Belgian Blue (Cattle) (VBO_0000139).
Breeds in which the phene or likely causal variants have been documented. If a likely causal variant has been documented, see variant-specific breed information in the variant table. (Breed information may be incomplete).

Associated gene: