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. 2005 Jun 16;6:34.
doi: 10.1186/1471-2156-6-34.

Polymorphisms Within the Canine MLPH Gene Are Associated With Dilute Coat Color in Dogs

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Free PMC article

Polymorphisms Within the Canine MLPH Gene Are Associated With Dilute Coat Color in Dogs

Ute Philipp et al. BMC Genet. .
Free PMC article

Abstract

Background: Pinschers and other dogs with coat color dilution show a characteristic pigmentation phenotype. The fur colors are a lighter shade, e.g. silvery grey (blue) instead of black and a sandy color (Isabella fawn) instead of red or brown. In some dogs the coat color dilution is sometimes accompanied by hair loss and recurrent skin inflammation, the so called color dilution alopecia (CDA) or black hair follicular dysplasia (BHFD). In humans and mice a comparable pigmentation phenotype without any documented hair loss is caused by mutations within the melanophilin gene (MLPH).

Results: We sequenced the canine MLPH gene and performed a mutation analysis of the MLPH exons in 6 Doberman Pinschers and 5 German Pinschers. A total of 48 sequence variations was identified within and between the breeds. Three families of dogs showed co-segregation for at least one polymorphism in an MLPH exon and the dilute phenotype. No single polymorphism was identified in the coding sequences or at splice sites that is likely to be causative for the dilute phenotype of all dogs examined. In 18 German Pinschers a mutation in exon 7 (R199H) was consistently associated with the dilute phenotype. However, as this mutation was present in homozygous state in four dogs of other breeds with wildtype pigmentation, it seems unlikely that this mutation is truly causative for coat color dilution. In Doberman Pinschers as well as in Large Munsterlanders with BHFD, a set of single nucleotide polymorphisms (SNPs) around exon 2 was identified that show a highly significant association to the dilute phenotype.

Conclusion: This study provides evidence that coat color dilution is caused by one or more mutations within or near the MLPH gene in several dog breeds. The data on polymorphisms that are strongly associated with the dilute phenotype will allow the genetic testing of Pinschers to facilitate the breeding of dogs with defined coat colors and to select against Large Munsterlanders carrying BHFD.

Figures

Figure 1
Figure 1
Blue Doberman Pinscher und black-and-tan Doberman Pinscher. Blue Doberman Pinscher (A) and black-and-tan Doberman Pinscher (B). Note the coat color differences between the two animals. The black and reddish fur parts of the black-and-tan Doberman Pinscher are changed to paler coloring in the blue dog. Classical genetics states that the blue dog is homozygous for the recessive dilute allele (d).
Figure 2
Figure 2
Architecture of the canine MLPH gene. (A) The 48 polymorphisms that were identified in Doberman Pinschers and/or German Pinschers are indicated. PCR products spanning each of the MLPH exons with adjacent flanking sequences were sequenced. The eight SNPs around exon 2 show strong association with the dilute allele in Doberman Pinschers, however they are monomorphic in German Pinschers. The R199H mutation shows strong association with the dilute allele in German Pinschers and in some Doberman Pinschers of European origin. (B) Genomic organization of the canine MLPH gene. Exons are denoted as boxes. Solid boxes represent coding sequence while open boxes contain the untranslated regions. The genomic section corresponds to a 50 kb interval in the analyzed sequence of 212.696 bp (positions 156.001 – 206.000). (C) Illustration of the unusually high GC-content of the canine MLPH gene. The GC-content was calculated using a 300 bp window. CpG island criteria were: GC > 0.5, CpGobs/CpGexp > 0.6, and length > 200 bp.
Figure 3
Figure 3
Alignment of MLPH proteins from different species. The MLPH protein sequences were translated from nucleotide database accessions [EMBL:AJ920333] (dog), [Genbank:AK022207] (human), [Genbank:AF384098] (mouse), and [Genbank:BC081894] (rat), respectively. The three major predicted protein domains of MLPH are indicated in accordance with [24]. Note the 13 additional amino acids in the dog MLPH protein encoded by dog exon 5, which is not conserved in other species. Another big difference between the sequences is caused by the fact that dog is lacking a homologous exon to human exon 9. In human this exon is not used constitutively and for the alignment a protein isoform without the amino acids encoded by this alternative exon was used. Polymorphisms that affect the amino acid sequence of the dog MLPH protein are indicated with arrows. None of the observed protein polymorphisms has a segregation pattern in the investigated families that would be compatible with a causative mutation for dilute.
Figure 4
Figure 4
Selected families and MLPH genotyping data. (A) Doberman Pinscher family of American origin that was used in the initial mutation analysis. Dilute animals (dd) are indicated as solid black symbols. Animals 1 and 2 are obligate heterozygotes for dilute as they were black-and-tan with blue offspring. Animals 4 and 6 were classified DD and Dd based on their MLPH exon 2 genotypes. Genotypes for the seven polymorphic amino acid positions in the MLPH protein and the silent C/T SNP in exon 2 of the MLPH gene are shown. Three different marker haplotypes are color-coded. (B) Animals 8–12 of the depicted German Pinscher family were used for the initial mutation analysis. Animals 7 and 8 are obligate heterozygotes for dilute as they were black-and-tan with blue offspring. Animals 10 and 12 were classified as Dd based on their genotypes with respect to the R199H mutation. (C) Large Munsterlander family used in this study. Black symbols indicate dogs with dilute coat color and BHFD. Animals 14 and 15 are obligate heterozygotes for dilute and BHFD as they were normal with BHFD offspring. Classification of the animals 13 and 16–20, respectively, was done based on their MLPH exon 2 genotypes.
Figure 5
Figure 5
Genotyping of the R199H mutation. (A) Schematic diagram of the HhaI RFLP used for genotyping the R199H mutation. (B) Genotyping of the R199H mutation in Doberman Pinschers and German Pinschers. Numbers of the animals correspond to the numbers in Fig. 3A and 3B. Note that the Doberman Pinschers are homozygous for the presumed wildtype allele (199R) while in the studied German Pinscher family the R199H mutation cosegregates with the d allele.

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