A novel <scp>MLPH</scp> variant in dogs with coat colour dilution

Bauer, Anina; Kehl, Alexandra; Jagannathan, Vidhya; Leeb, Tosso

doi:10.1111/age.12632

Cited by 29 publications

(47 citation statements)

References 21 publications

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“…The white fur of harlequin Great Danes is attributed to melanocyte death, likely resulting from failure of the impaired proteasome to degrade aberrant PMEL produced during development [ 15 ]. Unrelated to the merle phenotype is a uniform dilute coat caused by recessive mutations in MLPH that occur in several dog breeds [ 16 , 17 ].…”

Section: Introductionmentioning

confidence: 99%

Length variations within the Merle retrotransposon of canine PMEL: correlating genotype with phenotype

et al. 2018

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BackgroundThe antisense insertion of a canine short interspersed element (SINEC_Cf) in the pigmentation gene PMEL (or SILV) causes a coat pattern phenotype in dogs termed merle. Merle is a semi-dominant trait characterized by patches of full pigmentation on a diluted background. The oligo(dT) tract of the Merle retrotransposon is long and uninterrupted and is prone to dramatic truncation. Phenotypically wild-type individuals carrying shorter oligo(dT) lengths of the Merle allele have been previously described and termed cryptic merles. Two additional coat patterns, dilute merle (uniform, steely-grey coat) and harlequin merle (white background with black patches), also appear in breeds segregating the Merle allele.ResultsSequencing of all PMEL exons in a dilute and a harlequin merle reveals that variation exists solely within the oligo(dT) tract of the SINEC_Cf insertion. In fragment analyses from 259 dogs heterozygous for Merle, we observed a spectrum of oligo(dT) lengths spanning 25 to 105 base pairs (bp), with ranges that correspond to the four varieties of the merle phenotype: cryptic (25–55 bp), dilute (66–74 bp), standard (78–86 bp), and harlequin (81–105 bp). Somatic contractions of the oligo(dT) were observed in 43% of standard and 51% of harlequin merle dogs. A small proportion (4.6%) of the study cohort inherited de novo contractions or expansions of the Merle allele that resulted in dilute or harlequin coat patterns, respectively.ConclusionsThe phenotypic consequence of the Merle SINE insertion directly depends upon oligo(dT) length. In transcription, we propose that the use of an alternative splice site increases with oligo(dT) length, resulting in insufficient PMEL and a pigment dilution spectrum, from dark grey to complete hypopigmentation. We further propose that during replication, contractions and expansions increase in frequency with oligo(dT) length, causing coat variegation (somatic events in melanocytes) and the spontaneous appearance of varieties of the merle phenotype (germline events).Electronic supplementary materialThe online version of this article (10.1186/s13100-018-0131-6) contains supplementary material, which is available to authorized users.

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Section: Introductionmentioning

confidence: 99%

Length variations within the Merle retrotransposon of canine PMEL: correlating genotype with phenotype

et al. 2018

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“…Philipp et al (2005) found that a set of SNPs near exon 2 were identified that were highly significantly associated to the dilute phenotype. Bauer et al (2018) identified MLPH:c.705G>C as a variant explaining a second canine dilution allele. In a study of minks of violet and silver-blue colour, Cirera et al (2013) found that a phenotypic deletion in MLPH on exon 8 of the silver-blue mink resulted in the deletion of myosin VA (MYO5A) binding domain.…”

Section: Discussionmentioning

confidence: 99%

Association of Melanophilin (MLPH) gene polymorphism with coat colour in Rex rabbits

Chen

Liu

et al. 2020

World Rabbit Sci.

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Rex rabbit, with multiple phenotypes and colourful fur, is an interesting model for assessing the effect of coat colour gene mutations on characteristic pigmentation phenotype. Based on previous study, the melanophilin (MLPH) gene is a positional candidate gene related coat colour dilution. The fur colours are a lighter shade, e.g. grey instead of black. We sequenced 1689 base pairs of the MLPH gene in Chinchilla and black Rex rabbit. A total of 13 polymorphisms were identified, including seven missense mutations. The rabbit MLPH gene has a very high GC content and the protein shows 64.87% identity to the orthologous human protein (lack of homologous amino acids encoded by human MLPH exon 9). Hardy-Weinberg test showed that, except for the g.606C>A single nucleotid polymorphism (SNP), all other SNPs were in Hardy-Weinberg equilibrium. Haplotype analysis revealed that the seven missense mutation SNPs of two strains of Rex rabbits formed 10 haplotypes, but there were only seven major types of haplotypes (haplotype frequency P>0.05). The major haplotypes of the Chinchilla and black Rex rabbits were H1/H2/H3/H4/H5 and H1/H2/H3/H6/H8, respectively. The special haplotypes of Chinchilla Rex rabbit (H4, H5, H7) were consistently associated with the Chinchilla phenotype. This study provides evidence that different coat colour formation may be caused by one or more mutations within MLPH gene in several Rex rabbit strains. The data on polymorphisms that are associated with the Chinchilla phenotype facilitate the breeding of rabbits with defined coat colours.

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“…We confirmed the commercial laboratory results, where the dilute Italian greyhound and dilute pumis were heterozygous for d 1 and homozygous wild type for d 2 . At the same time, we identified a cytosine insertion subsequent to a run of 8 cytosine bases, (NM_001103219.2: c.667_668insC or chr25: g.48150749_50insC (CanFam 3.1 assembly), hereafter referred to as d 3 . No other variants altering the protein coding sequence were found.…”

Section: Mlph Exon Sequencingmentioning

confidence: 97%

A Third MLPH Variant Causing Coat Color Dilution in Dogs

Buren

Minor

Grahn

et al. 2020

Genes

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Altered melanosome transport in melanocytes, resulting from variants in the melanophilin (MLPH) gene, are associated with inherited forms of coat color dilution in many species. In dogs, the MLPH gene corresponds to the D locus and two variants, c.−22G > A (d1) and c.705G > C (d2), leading to the dilution of coat color, as described. Here, we describe the independent investigations of dogs whose coat color dilution could not be explained by known variants, and who report a third MLPH variant, (c.667_668insC) (d3), which leads to a frameshift and premature stop codon (p.His223Profs*41). The d3 allele is found at low frequency in multiple dog breeds, as well as in wolves, wolf-dog hybrids, and indigenous dogs. Canids in which the d3 allele contributed to the grey (dilute) phenotype were d1/d3 compound heterozygotes or d3 homozygotes, and all non-dilute related dogs had one or two D alleles, consistent with a recessive inheritance. Similar to other loci responsible for coat colors in dogs, this, alongside likely additional allelic heterogeneity at the D locus, or other loci, must be considered when performing and interpreting genetic testing.

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A novel MLPH variant in dogs with coat colour dilution

Cited by 29 publications

References 21 publications

Length variations within the Merle retrotransposon of canine PMEL: correlating genotype with phenotype

Length variations within the Merle retrotransposon of canine PMEL: correlating genotype with phenotype

Association of Melanophilin (MLPH) gene polymorphism with coat colour in Rex rabbits

A Third MLPH Variant Causing Coat Color Dilution in Dogs

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