MLPH Genotype--Melanin Phenotype Correlation in Dilute Dogs

Abstract

Coat color dilution in dogs is a specific pigmentation phenotype caused by a defective transport of melanosomes leading to large clumps of pigment. It is inherited as a Mendelian autosomal recessive trait and may be accompanied by hair loss, the so-called color dilution alopecia (CDA), or black hair follicular dysplasia (BHFD). We previously identified the noncoding c.-22G>A transition in the melanophilin gene (MLPH) as a candidate causative mutation for the dilute phenotype. We have now extended our study and genotyped 935 dogs from 20 breeds segregating for dilute coat color. The dilute-associated A allele segregates in many different breeds suggesting an old mutation event. We also investigated skin biopsies of dogs suspected of having either CDA or BHFD, and our data clearly indicate that the dilute mutation is required but not sufficient to develop clinical signs of the disease. The risk to develop CDA/BHFD seems to be breed specific. Interestingly, 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.

Full text

Journal of Heredity
doi:10.1093/jhered/esp010
ÓThe American Genetic Association. 2009. All rights reser ved.
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MLPH Genotype—Melanin Phenotype
Correlation in Dilute Dogs
M. WELLE,U.PHILIPP,S.RU
¨FENACHT,P.ROOSJE,M.SCHARFENSTEIN,E.SCHU
¨TZ,B.BRENIG,M.LINEK,
L. MECKLENBURG,P.GREST,M.DRO
¨GEMU
¨LLER,B.HAASE,T.LEEB,AND C. DRO
¨GEMU
¨LLER
From the Institute of Genetics, Vetsuisse Faculty, University of Berne, Bremgartenstrasse 109a, 3001 Berne, Switzerland
(Haase, Leeb, M. Dro¨ gemu
¨ller, and C. Dro¨ gemu
¨ller); the Institute of Animal Breeding and Genetics, University of Veterinary
Medicine Hannover, Bu
¨nteweg 17p, Hannover, Germany (Philipp); the Institute of Animal Pathology, Vetsuisse Faculty,
University of Berne, La¨nggassstr. 122, Berne, Switzerland (Welle); the Division of Clinical Dermatology, Department of
Clinical Veterinary Medicine, Vetsuisse Faculty, University of Berne, La¨nggassstr. 128, Berne, Switzerland (Ru
¨fenacht and
Roosje); the Institute of Veterinary Medicine, University of Go¨ ttingen, Burckhardtweg 2, Go¨ttingen, Germany
(Scharfenstein, Schu
¨tz, and Brenig); the Tiera¨rztliche Spezialisten, Rodigallee 85/Holstenhofweg, Hamburg, Germany (Linek);
the Consultant Veterinary Pathology, Bellevue 23, Hamburg, Germany (Mecklenburg); the Institute of Veterinary Pathology,
Vetsuisse Faculty, University of Zu
¨rich, Winterthurerstr. 268, Zu
¨rich, Switzerland (Grest); and the Dermfocus, Vetsuisse
Faculty, University of Berne, Berne, Switzerland (Haase, Leeb, C. Dro¨ gemu
¨ller, Welle, Ru
¨fenacht, and Roosje).
Address correspondence to Prof. Dr. Tosso Leeb, Institute of Genetics, Vetsuisse Faculty, University of Berne,
Bremgartenstrasse 109a, 3001 Berne, Switzerland, or e-mail: tosso.leeb@itz.unibe.ch.
Abstract
Coat color dilution in dogs is a specific pigmentation phenotype caused by a defective transport of melanosomes leading to large
clumps of pigment. It is inherited as a Mendelian autosomal recessive trait and may be accompanied by hair loss, the so-called
color dilution alopecia (CDA), or black hair follicular dysplasia (BHFD). We previously identified the noncoding c.-22G.A
transition in the melanophilin gene (MLPH) as a candidate causative mutation for the dilute phenotype. We have now extended
our study and genotyped 935 dogs from 20 breeds segregating for dilute coat color. The dilute-associated A allele segregates in
many different breeds suggesting an old mutation event. We also investigated skin biopsies of dogs suspected of having either
CDA or BHFD, and our data clearly indicate that the dilute mutation is required but not sufficient to develop clinical signs of
the disease. The risk to develop CDA/BHFD seems to be breed specific. Interestingly, 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.
Key words: black hair follicular dysplasia,coat color,color dilution alopecia,dog,melanophilin
Dogs with dilute coat color are known in many breeds. In
dilute dogs, the eumelanin- or phaeomelanin-pigmented skin
appears paler and is denoted breed specific, foe example,
blue, gray, Isabella, fawn, silver, or pale brown (Schmutz and
Berryere 2007). As the change in phaeomelanin is not as
dramatic as the eumelanin dilution, red-colored dogs are
sometimes difficult to detect as dilute. Coat color dilution (d)
is inherited as a Mendelian autosomal recessive trait in various
dog breeds (Schmutz et al. 1998). Coat color dilution is
characterized by a defective transport of melanosomes within
follicular melanocytes, which is mainly regulated by 3
interacting proteins (MLPH, MYO5A, and RAB27A) (Barral
and Seabra 2004; Hume et al. 2006; Hume et al. 2007). The
dilution phenotype occurs in different mammalian species,
and causative mutations within the melanophilin gene
(MLPH) have been identified in, for example, human,
mouse, and cat (Matesic et al. 2001; Me´nasche´ et al. 2003;
Ishida et al. 2006). In a previous study, we applied a candidate
gene approach and showed that dilute dogs from different
breeds share a common approximately 10-kb haplotype block
at the 5’ end of the MLPH gene. Within this shared haplotype
block, a noncoding single nucleotide polymorphism (SNP) at
the splice donor of exon 1 (c.-22G.A) represents a candidate
causal mutation for coat color dilution in 7 dog breeds. The
MLPH mRNA expression in skin biopsies of dilute beagles
carrying the mutant A allele was lower than in beagles
carrying the wild-type G allele (Philipp, Hamann, et al. 2005;
Philipp, Quignon, et al. 2005; Dro
¨gemu
¨ller et al. 2007).
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Coat color dilution has been described as a predisposing
risk factor for certain forms of hair loss in dogs (Mecklenburg
2006). Both, color dilution alopecia (CDA; also known as
color mutant alopecia) and black hair follicular dysplasia
(BHFD), also known as dark hair follicular dysplasia
(Selmanowitz et al. 1972), are primarily noninflammatory
forms of hair loss that occur in various dog breeds. CDA is
associated with a dilute coat color (Laukner 1998), and hair
loss is usually most severe on the dorsal trunk. BHFD occurs
in the pigmented coat areas of spotted dogs, for example, in
the Large Munsterlander (Schmutz et al. 1998). Some authors
consider both diseases to be etiologically identical (Carlotti
1990). BHFD is usually clinically noted within the first weeks
of age and comprises fracture of hair shafts in dark coated
regions, resulting in partial alopecia and scaling. First clinical
signs of CDA are usually noticed between 3 and 12 months of
age, rarely later in life, and lesions are usually slowly
progressive with age. Affected dogs are prone to secondary
pyoderma. With regard to histopathology, CDA is identical to
BHFD (Gross et al. 2005, Mecklenburg 2006). Affected skin
reveals large clumps of melanin within melanocytes in the
hair matrix, the outer root sheath of the hair follicle, and
within the hair shaft. The affected hair shafts frequently break
within the hair canal resulting in a more or less distorted
follicular infundibulum, which is often plugged with keratin,
fragmented hairs, and large irregular clumps of melanin. The
amount of clumped melanin is variable among breeds and
individuals and so is the expressivity of clinical disease
(Hargis et al. 1991; Mecklenburg 2006). Some dogs with
exactly the same histological findings in the hair follicles have
no signs of alopecia, whereas others may have complete hair
loss. About 25% of the gray/blue dogs of both sexes show
clinical symptoms, whereas the others do not develop
alopecia. In addition, not all dogs that have symptoms
develop them at a similar age of onset or with similar severity
(Schmutz and Berryere 2007). Obviously, some dog breeds,
for example, the Large Munsterlander (von Bomhard et al.
2006), develop more easily clinical symptoms than other
breeds, such as the Weimaraner, where if symptoms occur at
all, they are less pronounced (Laffort-Dassot et al. 2002;
Schmutz and Berryere 2007). Unfortunately, no comprehen-
sive study on the breed distribution of CDA or BHFD has
been published. A possible influence of other genes besides
MLPH influencing the expressivity of clinical disease is under
debate, and recently the canine RAB27A gene was analyzed
as possible candidate gene. However, no indication for
associated nucleotide polymorphisms in the coding region of
RAB27A was found (Schmutz and Berryere 2007).
We now conducted an extensive screening experiment to
survey in which breeds the MLPH c.-22G.A mutation
occurs and for which of the various coat colors in different
breeds this mutation might be causative. We also in-
vestigated the MLPH genotypes and the histopathological
findings in skin biopsies of 45 dogs suspected of having
either CDA or BHFD in order to develop an improved
phenotypic classification of CDA and a better understand-
ing for additional disease-promoting factors apart from coat
color dilution.
Materials and Methods
MLPH c.-22G.A SNP Genotyping
DNA prepared from ethylenediaminetetraacetic acid
(EDTA)–stabilized blood samples of 935 purebred individ-
uals was available for genotyping. These dogs were from 20
breeds, in which the dilute phenotype occurs (Table 1). The
coat color phenotype of the dogs was recorded based on
photographs and/or pedigree certificates as described
(Philipp, Hamann, et al. 2005). Additionally, paraffin-
embedded skin biopsies of 45 dogs with melanin aggregates
within the hair follicles were available. The skin biopsies
were from 40 purebred dogs and from 5 mongrels (Table 2).
DNA was isolated from the skin biopsies using the DNeasy
Blood and Tissue Kit following the manufacturer’s
instructions (Qiagen, Hombrechtikon, Switzerland).
Polymerase chain reaction (PCR) for amplifying a 312-bp
fragment containing canine MLPH exon 1 using the primers
MLPH_157395_F (5#-CCTTCCTTCCCCTGTAGGAC-
3#) and MLPH_157706_R (5#-GCCTAAAAT-
GAGCTCCCTGA-3#) and sequence reactions were carried
out as described before (Dro
¨gemu
¨ller et al. 2007). Sequence
data were analyzed with Sequencher 4.8 (GeneCodes, Ann
Arbor, MI) to derive the genotypes at the MLPH c.-22G.A
polymorphism. Alternatively, the PCR reaction was carried
out using the same primers in a LightCycler where a melting
point analysis was performed after amplification using the
sensor oligonucleotides Dil(AiO)E1Pw (5#-ROX-GAA
AGG AGC CGG TGA GTG CA-PHO-3’), Dil(AiO)E1Pm
(5#-Cy5.5-GAA AGG AGC CAG TGA GTG CAG-PHO-
3#), and the anchor oligonucleotide Dil(AiO)Ex1A (5#-CCA
GGG CCT GCC CGC CCC G-fluoresceine-3#). The mutation
is characterized by a sensor probe half melting tempera-
ture of 60 °C (Dil(AiO)E1Pw) or 67 °C (Dil(AiO)E1Pm) as
compared with 66 °Cor61°C for the wild-type allele,
respectively.
Histopathology
One to five routinely processed skin biopsies stained with
hematoxylin and eosin from a total of 45 dogs were
examined in this study. They were selected from archival
material of the Institute for Animal Pathology, Vetsuisse
Faculty, University of Berne, Berne, Switzerland (35 cases),
and the Institute of Veterinary Pathology, Vetsuisse Faculty,
University of Zu
¨rich, Zu
¨rich, Switzerland (10 cases). In all
histological reports of these biopsies, clumped melanin in
the hair follicle and hair shafts had been described. For this
study, a blinded histological examination of the biopsies was
performed by one of the authors.
Results and Discussion
In a previous study, we have identified the c.-22G.A
transition at the last nucleotide of the 5#-untranslated first
exon of the MLPH gene as a candidate causative mutation
for the dilute phenotype (Dro
¨gemu
¨ller et al. 2007). We have
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now extended our study and genotyped 935 dogs with
recorded coat color from 20 different dog breeds at this SNP
marker (Table 1). In 9 of the 20 dog breeds, informative 2-
generation families were available, and in these families the A
allele showed perfect cosegregation with the dilute pheno-
type. Furthermore, we observed perfect association of the
dilute phenotype with the c.-22G.A polymorphism in all 20
different breeds, and each of the 112 dilute colored dogs in
our study was homozygous for the A allele at the c.-22G.A
polymorphism (Table 1). We still cannot formally exclude the
possibility that c.-22G.A represents just a neutral poly-
morphism in linkage disequilibrium with the causative
mutation until the complete associated haplotype block has
been fully characterized in the dilute animals. However, the
new genotype data from the extended large cohort are in
agreement with our previous findings and support the
hypothesis that c.-22G.A is indeed the causative mutation.
The wide breed distribution across diverse types of dogs
implies an old mutation event predating the creation of
modern dog breeds.
Dilute colored dogs are assumed to be predisposed to
develop hair loss in the form of CDA or BHFD. In order to
get a more accurate phenotypic classification, we histolog-
ically examined archived biopsies of 45 unrelated dogs with
an original histological finding of clumped melanin within
the hair follicle and clinical hair loss. On re-evaluation in 29
of the 45 cases, the clinical findings were compatible with
the described findings in CDA or BHFD (Gross et al. 2005).
In all 45 cases, clumped melanin of variable size in the hair
shaft and the outer root sheath of the follicle was present.
Some hair shafts were fractured or attenuated. The
sometimes dilated infunbibula contained variable amounts
of keratin, hair fragments, and melanin clumps. A rather
high percentage of hair follicles was in telogen, and
perifollicular pigmentary incontinence of variable degree
was present. In some of the biopsies, additional findings
Table 1. Genotype frequencies of the MLPH c.-22G.A SNP in 935 dogs with Coat color records
Breed Coat color No. of animals
Exon 1 SNP (c.-22G.A)
A/A A/G G/G
German pinscher
a
Dilute 28 28
Wild type 363 131 232
Doberman pinscher
a
Dilute 26 26
Wild type 208 77 131
Rhodesian ridgeback
a
Dilute 8 8
Wild type 112 35 77
Whippet Dilute 11 11
Wild type 64 38 26
Australian shepherd
a
Dilute 3 3
Wild type 21 8 13
Briard
a
Dilute 6 6
Wild type 12 6 6
Bolonka Zwetna
a
Dilute 3 3
Wild type 11 9 2
French bulldog Dilute 2 2
Wild type 11 6 5
Great Dane Dilute 3 3
Wild type 5 2 3
Chihuahua Dilute 4 4
Wild type 3 3
Beagle
a
Dilute 2 2
Wild type 5 4 1
Large Munsterlander
a
Dilute 2 2
Wild type 4 4
Newfoundland Dilute 2 2
Wild type 2 1 1
Hovawart Dilute 2 2
Wild type 2 2
Miniature pinscher Dilute 3 3
Border collie Dilute 2 2
Slovakian rough haired pointer Dilute 2 2
American Staffordshire terrier Dilute 1 1
Italian greyhound Dilute 1 1
Jack Russel terrier Dilute 1 1
Total 935 112 326 497
a
Perfect cosegregation of the A allele with the dilute coat color was also observed in informative families of these breeds.
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compatible with a secondary pyoderma were seen. The 45
biopsies were also genotyped at the MLPH c.-22G.A SNP.
The coat color phenotypes of the 45 dogs were not available.
A total of 38 out of 45 dogs were homozygous A/A for the
dilute-associated allele. Two dogs with aggregated melanin
within the hair follicles and hair shafts were heterozygous
A/G, and 5 dogs were homozygous G/G. Surprisingly,
some clumped melanin was present in the outer root sheath
of the follicles in these 7 dogs. However, clumping of
melanin is not only specific for CDA and BHFD but also
occurs in hair follicle dystrophy as a consequence of
preterminal catagen induction (Hendrix et al. 2005). All
remaining 38 homozygous A/A cases showed clumped
melanin in the hair follicles. In 22 dogs (58%), where the
clinical anamnesis was exactly compatible with the criteria of
CDA or BHFD, clumped melanin was visible in the
epidermis (Figure 1a). In 7 dogs (18%), which also showed
typical clinical symptoms of CDA or BHFD, the clumped
melanin could only be seen in the hair follicles, and we
consider these dogs to be most likely affected with CDA or
BHFD (Figure 1b). In the remaining 9 dogs (24%), where
the clumped melanin was also apparently restricted to the
hair follicles, the clinical symptoms were not compatible
with CDA or BHFD after careful re-evaluation of the
available anamneses (Figure 1c). In some of these dogs, the
re-evaluation resulted in the diagnosis of other well-known
hair loss phenotypes, such as, for example, seasonal flank
alopecia or endocrine disorders.
Table 2. Histological phenotypes of 38 biopsies from dogs, which were homozygous A/A at MLPH c.-22G.A and originally
suspected of being affected with CDA or BHFD
Breed
No. of
animals
Clinically CDA/BHFD
and clumped melanin in
epidermis and follicle
Clinically CDA/BHFD
and clumped melanin
only in follicle
Clinically other forms
of alopecia and clumped
melanin only in follicle
Doberman pinscher 7 4 3
Yorkshire terrier 7 5 2
German pinscher 2 2
Chihuahua 5 3 1 1
Rhodesian ridgeback 2 2
Staffordshire bull terrier 1 1
Bernese mountain dog 1 1
Giant schnauzer 1 1
Great Dane 1 1
Italian greyhound 1 1
Miniature pinscher 1 1
Poodle 1 1
Prague Ratter 1 1
Tibetan terrier 1 1
Weimaraner 1 1
Mongrels 5 4 1
Total 38 22 (58%) 7 (18%) 9 (24%)
Figure 1. Representative histological phenotypes of dogs, which were homozygous A/A at MLPH c.-22G.A and suspected of
being affected with CDA or BHFD. Biopsies from dogs with (a) confirmed clinical symptoms of CDA/BHFD and clumped
melanin in epidermis, hair follicles, and hair shafts; (b) clinical symptoms compatible with CDA/BHFD and clumped melanin only
in the hair follicle; and (c) clinical symptoms different from accepted CDA/BHFD criteria and clumped melanin restricted to the
hair follicle. Note that melanin clumping in the hair follicle is similar in all 3 cases, and the definitive diagnosis of CDA/BHFD can
only be made based on additional clinical findings. Hematoxylin and eosin 200.
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From the detailed histological analysis of the 38 biopsies
from homozygous A/A dogs, we suspect that the current
histopathological diagnostic criterium of clumped melanin in
the hair follicle does not allow an unambiguous phenotype
classification of clinically suspected CDA or BHFD cases.
The histhopathological findings have to be evaluated in light
of the clinical symptoms to allow a precise and definitive
diagnosis of CDA or BHFD. In about a quarter of the dogs
that had originally been diagnosed with CDA or BHFD, the
hair loss is apparently caused by a different pathological
mechanism, and therefore, these dogs should not be
considered to be genuinely affected by CDA or BHFD.
According to our findings, clumped melanin in the epidermis
is a very strong indicator of true CDA or BHFD.
In conclusion, we found perfect association of the
MLPH c.-22G.A SNP with dilute coat color in more than
900 dogs supporting the hypothesis that this polymor-
phism is indeed the causative mutation. The wide breed
distribution of the mutant MLPH c.-22G.A allele
suggests an old mutation event. Although our data clearly
indicate that the MLPH mutation increases the risk for
CDA/BHFD, there seem to be additional modifying
factors. A characteristic feature of most CDA/BHFD–
affected dogs is the presence of clumped melanin in the
epidermis. In some breeds, such as the pinscher breeds and
the Rhodesian ridgebacks, the reported coat quality of
dilute dogs ranges from normal to severely CDA affected.
Therefore, these breeds offer the chance to search for
modifier genes, which influence the risk of developing
CDA/BHFD in dogs with dilute coat color.
Funding
Albert-Heim-Foundation (grant no. 85).
Acknowledgments
The authors would like to thank the numerous owners, breeders, and
veterinarians who contributed samples to this study. The help of Brigitta
Colomb, Manuela Bozzo, Erika Garchi, and Evelyne Rohrer for expert
technical assistance is acknowledged.
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Accepted February 25, 2009
Corresponding Editor: Francis Gailbert
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