In other species: dog , cattle , domestic cat , rabbit , sheep

Categories: Pigmentation phene

Possibly relevant human trait(s) and/or gene(s)s (MIM numbers): 609227 (trait) , 606526 (gene)

Links to MONDO diseases:

• MONDO:0012220: Griscelli syndrome type 3

Mendelian trait/disorder: yes

Mode of inheritance: Autosomal recessive

Considered a defect: no

Key variant known: yes

Year key variant first reported: 2013

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: Silver-blue coat colour

Species-specific symbol: p

History: As summarised by Manakhov et al. (2019): "The first mink fur-colour mutant was described in 1931 [Трапезов & Трапезова, 2009; Liu et al., 2017], inherited as a Mendelian autosomal recessive trait and characterized by a Silverblue shade of the coat . . . . The mutation was originally named platinum due to similarity with an existing phenotype in foxes. Subsequently, the name was changed to Silverblue, although the mutation is still referred to as p [Трапезов & Трапезова, 2009]. This coat colour rose in popularity for the next 80 years, until it became one of the most common mutations in the mink fur industry."

Inheritance: The silver-blue coat colour, which is analogous to the dilute phenotype in other species, is inherited as an autosomal recessive at the Silver locus (Anistoroaei and Christensen, 2007). The symbol for the recessive allele is p.

Mapping: Anistoroaei and Christensen (2007) linkage-mapped this locus to chromosome NVI13, and showed that this locus was coincident with "A Canis familiaris BAC clone containing the melanophilin gene (which generates 'silver-like' phenotype in dog)", strongly suggesting that the silver locus in American mink is the MLPH locus. Using three microsatellites from a contig containing MLPH, Cicera et al. (2013) confirmed these results by linkage-mapping all three markers to the appropriate region of chromosome NVI3. They also reported physically mapping one of the microsatellites to NVI3q1.3-2.2.

Molecular basis: By sequencing the positional candidate MLPH gene (see mapping section above) in silverblue, violet and wild-type mink, Cirera et al. (2013) "identified two deletions of the entire intron 7 and of the 5′ end of intron 8 in the sequence of the Silverblue MLPH gene". Investigation of MLPH mRNA revealed that "the Silverblue animals completely lack exon 8, which encodes 65 residues, of which 47 define the Myosin Va (MYO5A) binding domain. This may cause the incorrect anchoring of the MLPH protein to MYO5A in Silverblue animals, resulting in an improper pigmentation as seen in diluted phenotypes." Interestingly, even though the silverblue allele lacks the entire exon 8, it has "retained part of the intron 8 in the coding region. This introduces a stop codon, leading to a truncated protein 284 residues long that is lacking almost all MYO5A Va and all actin-binding domains". In addition, the authors reported that "in the MLPH mRNA of wt, Violet and Silverblue phenotypes, part of intron 8 is retained resulting in a truncated MLPH protein, which is 359 residues long in wt and Violet and 284 residues long in Silverblue."

Manakhov et al. (2019) reported that the likely causal variant for the silverblue phenotype in mink "from two unrelated populations (Novosibirsk and Tver mink populations)" is "a single nucleotide variation (GL896909.1:662639 G/A (MLPH C.901 + 1 G > A), hereinafter referred to as MLPH^p) at the splice donor site of melanophilin (MLPH) that potentially resulted in loss of function".

Associated gene: