Black hair follicular dysplasia, an autosomal recessive condition in dogs

Abstract

Using histology, a coat color abnormality and the subsequent hair loss were diagnosed as black hair follicular dysplasia. A pedigree analysis of an affected litter and literature review suggests that this is inherited as an autosomal recessive trait. The melanocyte stimulating hormone receptor gene is ruled out by using linkage analysis.

Full text

Black
hair
follicular
dysplasia,
an
autosomal
recessive
condition
in
dogs
Sheila
M.
Schmutz,
Jane
S.
Moker,
Edward
G.
Clark,
Rhonda
Shewfelt
Abstract
-
Using
histology,
a
coat
color
abnormality
and
the
subsequent
hair
loss
were
diagnosed
as
black
hair
follicular
dysplasia.
A
pedigree
analysis
of
an
affected
litter
and
literature
review
suggests
that
this
is
inherited
as
an
autosomal
recessive
trait.
The
melanocyte
stimulating
hormone
receptor
gene
is
ruled
out
by
using
linkage
analysis.
Resume
La
dysplasie
folliculaire
des
poils
noirs,
une
affection
autosomique
recessive
chez
le
chien.
A
l'histologie,
une
anormalite
de
couleur
du
pelage
et
une
perte
subsequente
de
poils
ont
ete
diagnostiquees
comme
etant
une
dysplasie
folliculaire
des
poils
noires.
L'analyse
genealogique
d'une
portee
affectee
ainsi
qu'une
revue
de
la
litterature
suggerent
que
l'affection
est
heritee
comme
trait
autosomique
recessif.
Le
gene
du
recepteur
de
l'hormone
melantrope
est
elimine
par
l'analyse
de
liaison
des
genes.
Can
Vet
J
1998;
39:
644-646
Black
hair
follicular
dysplasia
(BHFD)
is
a
condi-
tion
that
affects
several
breeds
of
dog,
including
bearded
collies,
border
collies,
Jack
Russell
terriers
(5),
and
salukis.
It
is
generally
observable,
by
astute
breeders,
at
2
wk
of
age.
It
bears
considerable
resem-
blance
to
color
mutant
alopecia
(1,5),
which
is
rela-
tively
common
in
Doberman
pinschers,
and
may
be
the
same
disorder.
The
litter
of
Large
Munsterlanders
described
in
this
report
was
born
on
October
20,
1996.
It
was
the
result
of
an
accidental
mating
of
a
brother
and
sister,
which
was
allowed
to
go
to
term
in
order
to
study
the
genetic
ram-
ifications.
Some
Large
Munsterlanders
are
heterozy-
gous
for
brown
and
white
coat
color,
since
they
were
split
from
German
longhaired
pointers
on
the
basis
of
this
color
variation
(11).
The
sire
and
dam
of
this
litter
were
black
and
white,
as
were
the
grandparents
who
were
both
imported
from
Germany.
When
the
pups
were
born,
4
of
the
9
littermates
were
grey
and
white
instead
of
black
and
white
(Figure
1).
By
about
2
wk
of
age,
the
hair
quality
in
the
grey
patches
was
evidently
different
from
that
in
the
white
patches.
The
grey
hair
was
shorter,
duller,
thinner,
and
more
brittle.
By
4
wk,
the
grey
areas
had
lost
hair,
pre-
sumably
due
to
breakage.
Wrinkles
in
the skin
and
pus-
tules
were
either
more
developed,
or
were,
at
least,
more
evident
in
these
denuded
grey
areas.
These
char-
acteristics
have
been
described
previously
(12).
The
eye
color
in
all
4
grey-and-white
pups
was
abnor-
mal.
Upon
eye-opening,
at
about
10
d
of
age,
the
blue
was
paler
than
that
of
the
normal,
black-haired
litter-
mates.
By
8
wk,
the
eyes
in
the
normal
pups
were
turn-
Department
of
Animal
and
Poultry
Science
(Schmutz,
Moker),
Department
of
Veterinary
Pathology
(Clark),
Department
of
Veterinary
Anatomy
(Shewfelt),
University
of
Saskatchewan,
Saskatoon,
Saskatchewan
S7N
5B5.
Address
correspondence
and
reprint
requests
to
Dr.
Sheila
Schmutz.
Funding
was
provided
by
National
Science
and
Engineering
Research
Council.
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Figure
1.
Pedigree
of
the
inbred
litter
of
Large
Munsterlanders.
Affected
pups
(shaded)
varied
in
severity
of
symptoms
asso-
ciated
with
black
hair
follicular
dysplasia.
Also
shown
is
a
diagramatic
represention
of
the
DNA
banding
pattern
for
each
pup
and
the
parents.
ing
brown,
while
those
in
the
abnormal
pups
were
either
turning
yellow
or
remaining
blue.
Eye
color
differ-
ences
have
not
previously
been
reported
as
part
of
this
condition.
At
31
d
of
age,
a
pup
(Figure
1
-
generation
III,
pup
No.
4)
was
euthanized
and
skin
biopsies
were
taken
for
histological
analysis.
Separate
samples
from
white
patches
and
grey
patches
were
analyzed.
Three
sec-
tions
of
a
white-haired
sample
showed
only
one
abnor-
mal
follicle.
This
single
follicle
was
a
black
follicle
and
showed
the
typical
clumping
of
melanosomes
in
the
hair
matrix
and
hair
matrix
cells
of
the
bulb,
plus
an
abnormal
shape
of
the
hairshaft.
The
hairshaft
also
contained
numerous
melanosomes,
unlike
any
of
the
sur-
rounding
normal
white
hairshafts.
Very
mild
perivascular
mononuclear
cell
infiltrations
of
the
dermis
were
observed.
The
grey-haired
sample
showed
every
hair
fol-
licle
to
be
abnormal,
as
occurs
in
both
color
mutant
alopecia
and
BHFD.
The
hairshafts
were
irregular
in
con-
tour
and
heavily
pigmented;
many
were
eosinophilic,
rather
than
not
taking
up
the
eosin
stain
at
all,
as
occurs
normally.
The
bulbs
themselves
were
often
abnormal
in
size
and
shape,
with
clumps
of
melanosomes
and
Can
Vet
J
Volume
39,
October
1998
644

megamelanosomes,
which
are
common
in
the
lumen
of
the
more
superficial
follicles.
No
normal
hair
follicles
were
present,
yet
most
follicles
appeared
to
be
in
the
ana-
gen
rather
than
the
telogen
phase
of
growth.
Very
few
secondary
follicles
were
recognizable.
No
other
gross
or
microscopic
anomalies
were
detected
at
necropsy.
A
second
pup
(Figure
1-
generation
III,
pup
No.
3)
was
euthanized
at
7.5
wk.
Skin
samples
were
taken
and
shipped
to
another
laboratory
for
mRNA
extraction.
The
remaining
2
grey
pups
were
allowed
to
grow
to
12
wk,
beyond
the
time
most
pups
would
have been
placed
into
new
homes.
One
of
the
2
(Figure
1-
gen-
eration
III,
pup
No.
2)
was
recognized,
by
the
owners,
as
being
deaf
by
8
wk
of
age.
His
eyes
remained
pale
blue,
even
more
so
than
the
others.
Deafness
is
sometimes
associated
with
neural
crest
cell
migration
and
pigmentation,
as
reported
in
Dalmatians
(2).
Deafness
has
not
previously
been
reported
in
BHFD,
but
it
may
simply
have
been
missed,
as
nearly
occurred
in
this
litter.
It
likely
affects
only
a
small
proportion
of
pups
with
the
skin
disorder.
Data
reported
previously
(12)
suggested
that
BHFD
is
an
autosomal
recessive
condition;
this
was
subsequently
questioned
by
Lewis
(6),
since
3
of
15
pups
in
2
litters
from
a
mating
of 2
affected
parents
did
not
exhibit
the
skin
pathology.
However,
these
3
pups
were
all
white
and,
therefore,
could
not
show
pathology
in
black
skin
areas.
This
does
not
negate
that
BHFD
is
an
autosomal
recessive
condition,
since
based
on
our
findings,
the
white
skin
did
not
appear
to
be
affected.
Knottenbelt
and
Knottenbelt
(5)
deduced
that
BHFD
was
a
dominant
trait
by
using
the
data
from
Selmanowitz
et
al
(12).
However,
since
neither
parent
in
the
current
litter,
nor
the
parents
of
affected
pups
in
previous
reports,
were
affected,
dominance
can
be
ruled
out.
All
4
of
the
affected
pups
in
this
study
were
male,
which
might
suggest
that
this
is
a
sex-linked
condi-
tion.
However,
it
is
clearly
not
a
sex-linked
condition,
because
6
male
and
6
female
pups
were
affected
in
previous
litters
(12).
When
the
Large
Munsterlander
Club
in
Germany,
the
founding
organization
for
this
breed,
was
contacted,
we
learned
that
grey-and-white
pups
were
noted
as
early
as
1953.
The
affected
pups
were
euthanized
and
the
anomaly
was
not
diagnosed.
Although
BHFD
is
not
a
life-threatening
disorder,
large
skin
patches
with
no
hair
are
a
disadvantage
in
northern
climates.
Other
skin
disorders
in
dogs
with
BHFD
are
common
(3),
and
hearing
may
be
impaired,
as
in
one
of
these
pups.
Black
hair
color
has
been
attributed
to
the
E,
or
"extension"
locus,
as
an
autosomal
dominant
condi-
tion
(7).
Recently,
the
understanding
of
the
E
locus
has
been
further
refined
by
the
finding
that
it
encodes
melanocyte
stimulating
hormone
receptor
(MSHr)
in
cat-
tle
(4),
horses
(9),
pigs
(8),
foxes
(13),
mice
(called
MClr)
(10),
and
dogs
(14).
It
is
possible,
therefore,
that
a
mutation
at
this
locus,
which
influences
pigment
production
from
melanocytes,
might
be
responsible
for
BHFD,
causing
the
hair
to
be
grey
instead
of
black.
Carlotti
(1)
also
hypothesized
that
a
deficiency
in
the
MSH
could
be
the
cause
of
abnormal
melanization
in
both
BHFD
and
color
mutant
alopecia.
To
determine
if
this
might
be
the case,
we
compared
the
DNA
sequence
between
affected
and
unaffected
dogs
in
our
litter
(Figure
1).
Since
it
is
generally
accepted
that
many
coding
genes
share
considerable
DNA
homology
across
species,
we
used
polymerase
chain
reaction
primers
developed
for
cattle
for
a
portion
of
the
MSHr
gene
on
canine
DNA.
The
primer
set
from
cattle,
referred
to
as
P6/P7
(4),
yielded
a
532-bp
DNA
product
when
the
canine
DNA
was
amplified.
This
fragment
of
DNA
was
sequenced
using
an
automated
sequencer
(Applied
Biosystems,
Davis,
California,
USA)
and
was
compared
with
MSHr
sequences
from
other
species
in
Genbank,
a
DNA
data-
base.
This
canine
DNA
fragment
was
a
virtually
perfect
match
to
the
fox
sequence
(13),
base
pair
for
base
pair,
indicating
that
the
correct
gene,
that
is,
MSHr,
had
been
amplified.
Mutations
that
affected
coat
color
have been
found
in
several
species
in
this
portion
of
the
MSHr
gene,
though
no
two
at
the
same
base
pair
(13),
and
so
we
wished
to
examine
it
closely.
This
region
of
the
gene,
which
is
reported
to
affect
the
black
coloration,
was
also
sequenced
for
several
dogs,
including
the
sire,
the
dam,
and
the
affected
pup.
No
consistent
differences
were
detected
among
the
affected
pup,
his
parents,
or
in
any
unrelated,
normal
Large
Munsterlanders.
This
suggests
that
the
deviation
causing
BHFD
lies
elsewhere
in
the
gene
or
in
the
cellular
complex
affecting
coat
color
in
dogs.
Although
the
base
pair
change
causing
BHFD
was
not
located
in
the
portion
of
MSHr
amplified
in
our
exper-
iment,
some
other
differences
at
a
few
base
pairs
were
detected
among
the
various
dogs.
One
such
single
nucleotide
polymorphism
(SNP)
was
used
in
an
exper-
iment,
based
on
linkage,
to
determine
if
a
part
of
the
MSHr
gene,
other
than
the
one
we
had
sequenced,
might
harbor
the
causative
mutation
for
BHFD.
These
differences,
or
SNPs,
can
cause
restriction
enzymes
to
bind
and
cut
the
DNA
or
not
cut
it.
The
sire
of
this
litter
was
found
to
be
heterozygous
(Figure
1
shows
3
bands)
for
such
a
cut
site,
using
the
HhaI
restriction
enzyme,
at
base
pair
168.
The
dam
was
homozygous
and
her
DNA
did
not
cut;
therefore,
only
one
band
is
shown
(Figure
1).
This
polymorphism
could,
therefore,
be
used
to
determine
if
all
the
pups
exhibiting
BHFD
received
the
same
allele
(cut
or
not
cut)
from
their
sire.
Since
2
pups
did
receive
the
same
allele,
and
2
did
not,
linkage
of
BHFD
to
the
MSHr
gene,
or
to
genes
in
close
proximity
to
it,
can
also
be
ruled
out.
This
linkage
approach
of
using
a
family
of
dogs
with
the
disease
was
a
more
efficient
means
of
determining
if
MSHr,
or
any
mutation
within
about
1
million
base
pairs
of
the
gene
was
responsible
for
BHFD
than
trying
to
sequence
the
whole
gene,
especially
since
this
gene
can
now
be
ruled
out.
The
search
for
the
causative
gene
continues.
Acknowledgments
We
thank
Tom
Berryere
and Laura
Reader
for
assistance
with
DNA
sequencing.
cv.
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CORRECTION
Canine
coccidiosis
Gary
Conboy
Can
Vet
J
1998;
39:
443-444
Due
to
production
errors,
a
Diagnostic
Parasitology
column
was
published
with
inaccurate
information.
Figure
2
and
replacement
text
in
the
Discussion
are
reprinted
here.
The
editorial
staff
of
the
CVJ
apolo-
gizes
to
Dr.
Conboy
for
any
embarrassment
caused
by
the
errors,
and
to
our
readers.
Figure
2.
Isospora
ohioensis
-complex
oocysts
detected
on
a
zinc
sulfate
centrifugal
flotation
examination
of
feces
from
a
9-week-old
male
Welsh
springer
spaniel-
terrier
cross.
(256X
magnification,
Bar
=
50
microns).
Discussion
Coccidian
oocysts
detected
on
canine
fecal
exami-
nations
are
due
to
infection
with
one
or
more
of
4
species
of
Isospora
(I.
canis,
L
ohioensis,
I.
neori-
volta,
I
burrowsi)
and
1
species
of
Hammondia
(H.
heydomni)
(1,2).
Occasionally,
oocysts
of
Eimeria
spp.
are
detected
in
canine
feces
due
to
predation
on
infected
rabbits
or
rodents,
or
the
ingestion
of
rumi-
nant
fecal
matter.
Isospora
canis
oocysts
(Figure
3)
can
be
differentiated
from
the
others
based
on
their
larger
size
(34
to
42
pm
X
23
to
36
pm),
and
H.
heydorni
(Figure
4)
based
on
their
smaller
size
(1i3
PM
X
3
1PM).
646
Can
Vet
J
Volume
39,
October
1998