Download X-Linked Dominant Control of F-Cells in Normal

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X-Linked
of the
Dominant
Swiss
Type
Control
of F-Cells
in Normal
Adult
Life:
Characterization
as Hereditary
Persistence
of Fetal
Hemoglobin
Regulated
Dominantly
by Gene(s)
on X Chromosome
By Kazuo
Miyoshi,
Yoshikado
Kaneto,
Kiyoshi
Hasegawa,
Akira
Hisaomi
Fetal
nose
hemoglobin
(HbF) levels determined
in healthy Japaadults
ranged
from 0.3% to 1 6.0% as F cells and
0.1 7% to 2.28%
as HbF content,
which were the same as
those obtained
in other countries.
The frequency
distribution of 300 healthy
adults with various numbers
of F cells
consisted
statistically
of two different
groups. low and high
F-cell groups. Individuals
with 4.4%
of F cells (HbF about
0.7%)
were
defined
as
the
high
F-cell
trait,
which
accounted
for 1 1 .3% of males and 20.7% of females.
Family
studies
of 21 probands
with this trait and sex-different
frequency
analyses
in the
population
and
probands
revealed
X-Iinked
dominant
inheritance.
Two other fami-
L
ITTLE
IS KNOWN
hemoglobin
semia
(Hb)
and
extensively
recently
several
forms
increase
but different
base
transcription
by the
modest
HbF
authors
control
working
it is not clear
since
occurs
in the
linked,
From
Swiss
has
type
been
by
The
Medicine,
in this form of HPFH
First
The
not very
Department
University
Medical
Submitted
reprint
Department
of
a
Kuramoto-3,
The publication
costs ofthis
payment.
indicate
© 1988
to
accepted
Kazuo
Medicine,
of Tokushima,
This
article
in accordance
Okinaka
July
Memorial
Tokushima
article
must
with
MD,
ofMedicine,
therefore
First
The Univer-
be
section
in part
hereby
patterns,
HPFHs
be
the
of
0006-4971/88/7206-0156$03.OO/O
Inc.
also
indicate
the /3-globin
are supported
in some cases
of the region
around
the
/3-globin
gene
we
this
that
individuals
HPFH”
population
high
or whether
as the X chromo-
showed
constituted
than
F-cell
trait
was
a
previously
showed
X-linked
In our
preliminary
reports,
F-cell-type
HPFH
as a distinct
in terms
of its incidences
we
form,
and inheri-
but further
studies
led us to believe
that
reported
in the literature
as Swiss type would
same
type
as
with
those
obtained
ours.
We
describe
by other
of the Swiss
from
HbF
to
discussed
reference
gene
complex
such
genetic
characterization
developmental
switch
with
special
expression
our
data
in
researchers.
type
HbA
to the
by a trans-acting
The
HPFH
and
production
control
regulatory
the
are
of -y-globin
gene(s)
showing
inheritance
and located
on the X chromosome,
from the 13-globin gene cluster on chromosome
1 1.
MATERIALS
Population
and
Family
AND
METHODS
Studies
Healthy adults
among
the general
population,
doctors,
technicians, nurses, and students related to our department
were selected
at random and their blood was examined. Physical and hematologic
examinations
revealed no abnormalities.
Pregnant
females were
from
were included
the study.
in the study
Several
samples
as controls.
of umbilical
cord
For population
blood
study,
ISO
by page
men and 1 50 women
marked
years, but 90% of the individuals
were aged <40 years. For family
studies, the subjects in the population
study with high F-cell levels
1 734 solely
to
(described
& Stratton,
studies
far from
high-F-cell-type
Tokushima,’7”8
tance
similar
excluded
770, Japan.
were defrayed
18 U.S.C.
The
many
chromosome
of the
that
gene
of
of the
inheritance.
this high
dominant
separate
14, /988.
Miyoshi,
School
this fact.
by Grune
and
that
proportion
comparison
with
School
hand,
is localized
findings
analysis
on another
and
HPFH
Tokyo.
1 1, 1987;
requests
oflnternal
“advertisement”
Tokushima,
Medicine,
larger
dominant
described
linkage
analyses
HbS trait tentaof Swiss HPFH
to the /3-globin
of Internal
Research,
September
Address
tightly,
other
gene
as “adult
believed
an overlap
of F cells
Niki,
Inc.
some has not been determined.
In healthy
Japanese
adults,
far
interesting
or in the numbers
from
classifiable
increased
characterized
particularly
of HbF
although
Institutefor
1854
an apparent
trans-acting
facthere
is no direct
individuals.’
Nevertheless,
with thalassemia
and the
that the regulatory
gene(s)
of
charge
it is present
in
whether
levels
normal
of Swiss
HPFHs
tively conclude
those
sity
different
in
the
the
complex.”4
These
DNA
polymorphism
regions
substitutions
to cause
& Stratton.
the regulatory
showed
existed
Shinji
/3-globin
gene complex.’5”6
However,
whether
the regulatory
locus for the HPFHs
is located
in a chromosome
1 1 region
it is caused
by regulatory
genes
which
normally
the F-cell number
and the amount
of HbF. However,
out the genetics
of this condition
has been difficult
because
are
the
elevation9
by
point
showing
‘y-chain
production
by altering
a putative
tor’s binding
affinity,5’6’8
although
as yet
of this.
the HPFHs,
gene
(HbF)
levels,
such as in the
forms.8 These
substitutions
were
original
evidence
Among
of thalas-
studies
initiation
HPFH,
that
promotor
These
by Grune
complex)”#{176} On
determinants
have been
Ohchi,
Yamano
lies of the trait
associated
with
color blindness
were
described.
although
no definitive
evidence
for linkage was
obtained
between
the two. A review
of population
and
family
studies
reported
in the literature
indicated
that
persons
with Swiss-type
hereditary
persistence
of fetal
hemoglobin
(HPFH) are of the same kind as this trait in their
incidence
and inheritance
form. but represent
a portion of
the trait with higher levels of HbF or F cells. The existence
of X chromosome-localized
regulatory
gene(s)
for the
developmental
switch
of human
Hb production
is discussed.
human
hemoglobin
cis-acting
production,
genes.2
hemoglobin
and British
Greek,’7
proposed
fetal
the
globin
of nondeletion
in fetal
G..fl+3
genes,
-y-chain
single
5’ to the
studies
of
Hiroaki
and Toshinao
a 1988
regulating
to adult
many
particularly
/3-like
that
region
fetal
despite
regulatory
increased
of the
from
persistence
studied,
upstream
the
production,
The
for
the mechanisms
switch
hereditary
(HPFH).’
responsible
very
about
developmental
the
Kawai,
Shirakami,
probands
families
in
the
were selected;
Results
section)
they ranged
found
in age from
were
defined
17 to 65
as
the
at least both parents could be examined. Two other
were subjected to color blindness studies using lshihara
when
Blood,
Vol 72, No 6 (December),
1988:
pp 1854-1860
From www.bloodjournal.org by guest on June 16, 2017. For personal use only.
X-LINKED
plates
DOMINANT
and
F-cell
an
CONTROL
OF F-CELLS
anomaloscope,
analyses
as part
when
ofa
genetic
necessary,
linkage
1855
IN ADULTS
in addition
to
2.5
the
study.’9
Methods
2.0
Blood
collected
processed
examination.
within
two
blood
percentage
contents
of some
HbF.
of
HbF
Dozy
HbA2
was
HbF
were
solution
and
blood
was
at 4 to 5#{176}C
and
made
on
threefold
examined
for
immunofluorescent
samples
was
and
isolated
from
et al23’24 and
converted
against
mol/L
dialyzed
1.5
the
I
method.
were
measured
0.01
complete
adjuvant
of rabbits,
measured
by the
followed
every
to five weeks
after
and
HbA2
HbF
‘y-globulin
antisera
by
by
method
1.0
of
tography
with
week
blood films
reacted
were
with
37#{176}C
for
fixed
rabbit
for two
stained
with
and
0.1 mL
(Boehringer)
immersed
rabbit
in
(Nakarai)
lamp,
antisera
before
observed
with
use.
an
HBO-200)
(0.15
The
goat
anti-rabbit
fluorescence
and
anti-
liver
(Nikon,
powder
of RBCs
were
mercury
RBCs
showing
frequency
was
( I ,000
examined
RBCs).
Percentage,
The correlation
tent
measured
samples
HbF
The
average
but
the
females
and
Their
from
76
in Fig
healthy
1
.
content
ranged
from 0.5% to
respectively,
giving
a correlation
F-cell
Correlation
adults
(43
males,
percentage
12.6%
and
coefficient
and
irrespective
of each
33
0.17%
to 2.28%,
of 0.91. By the
individual’s
HbF
con-
tent.
Frequency
Counts:
The
females)
Distribution
Low-F-Cell
F-cell
counts
are shown
ofindividuals
and High-F-Cell
in 300
healthy
With
Various
percentage
of F cells
determined
and percentage of HbF content measured
of samples from 76 healthy adults; r = .91.
to 16.0%,
and
average
Analysis
two
different
fitted
for
a large
proportion
proportion
scattering
combining
both
counts
males
was
2.8%
centering
over
sexes
and
4.5%.
was 3. 1%,
the
average
of both sexes on distribution
using
the least-squares
method
showed
that
groups,
ie, the
to a theoretic
for
the
normal
distribution
main
was
composed
low-F-cell
distribution
were ana(Appen-
group
with
F-cell
of
which
percent-
0.7% (mean
± SD)
and the high-F-cell
group
considered
the outlier
to the main group,
although
age 2.2%
which was
±
the distribution
pattern
precisely
defined.
We
designation
Appendix.
The
two
of
the
F-cell
thus
F-cell
divided
as
were
<4.3%
4.4%,
described
termed
respectively.
or I 6.0%
ratio
subjects
was
ranged
(48
I : 1 .82. The
from
in
The
of 300)
F-cell
the
low-F-cell
and high-F-cell
subjects
high
for 1 1.3% (1 7 of 150) of males
of females,
male/female
group
counts
counts
accounted
high-F-cell
of the high-F-cell
group could not be
used F-cell percentage
4.4%
for the
high-F-cell
groups
having
(3 1 of 1 50)
The
with
a small
F-cell
F-cell
and 20.7%
of both
counts
sexes.
among
5.0% to 12.6% in males
and
8
III
results
20
HbF
same methods,
F-cell percentage
and HbF content
in 20
samples of umbilical
cord blood ranged from 95.7% to 98.8%
(97.2%
±
1.0%,
mean
± SD)
and
60.3%
to 76.3%
(67.2%
± 5.9%,
mean
± SD),
respectively.
HbA2 content
determined
in 18 of the healthy
adults
(seven males,
I1
females)
ranged
from I .8% to 3.4% of total Hb, giving
normal
between
Combined
data
lyzed
statistically
having
between
F-cell percentage
and HbF conby alkali denaturation
(AD)
of the same
is shown
15
was 3.4%.
subjects
obtained
females)
Content.
0.3%
2.0%
subjects
RESULTS
F-Cell
Correlation
from
around
dix).
‘y-globulin
goat
filter.
at
were
specimens
microscope
of the number
The
(1:9),
mg/mL)
bovine
were scored as F cells, and their
as a percentage
cells.
dehydrated,
with
an ultraviolet-activated
the
chroma-
FITC-labeled
absorbed
Fig 1 .
by immunofluorescence
by alkali denaturation
range
from
specimens
minutes,
glycerine.
were
four
anti-human
F
10
HbA
methanol/acetone
times.
50
HbF
with
column
of
5
U
toe pads
obtained
Immunofluorescence-stained
FL
with
green fluorescence
expressed
37#{176}Cfor
..
S F.cells
7.4).
-y-globulin
three
FITC-labeled
at
(pH
with
HbF
nonfluorescent
-y-globulin
cellulose
counting
minutes
washed
pH
was obtained
buffer
and
,..$
Freund’s
absorbed
and
HbF
ethanol
anti-human
then
of 1 mL
antisera
were
with
phosphate
was
into
injections
HbF
‘PI
0.5
(PBS,
with
injected
chromatography,
only
staining
50 minutes,
antisera
anti-human
diethylamino
mol/L
mg/mL)
immunization
reacted
Immunofluorescence
which
saline
initially
by booster
immunoaffinity
0.15
(2
was
against
by the method
azide, and stored at 5#{176}C
until
solution
Rabbit
by (DEAE)
antibodies
blood
to cyanmet-HbF
sodium
the initial
which
of
cord
phosphate-buffered
(Boehringer)
(1 mg/mL).
solution
raising
umbilical
7.2) containing
0.1% (wt/vol)
use. One milliliter
of HbF
then
stored
films
hemolysate
and
cord
et al.23’24
Purification
of
Blood
physiologic
denaturation,22
Dozy
bottles,
days.
with
or umbilical
of F cells#{176}’2’by an indirect
HbF
alkali
blood
in EDTA-containing
diluted
The
Venous
F-Cell
III
Males
A
1o
ii
20
30
40
50
6C
50
60
10
80
90
100
lU
12’O
33
140
150
10
80
90
100
II 0
70
130
40
150
60
:I
II
B
I
10
20
30
40
S
60
FcaBs
Subjects
adults
( I 50
in Fig 2. Both sexes showed
males,
a percentage
I 50
Fig 2.
Frequency distribution of individuals with various F-cell
counts. Results of 300 healthy adults (A. 1 50 males; B. 150
females). Vertical broken line: 4.4% F cells.
From www.bloodjournal.org by guest on June 16, 2017. For personal use only.
MIYOSHI
1856
4.5%
to 16.0%
in females.
HbF
content,
denaturation
in 76 subjects,
(average
0.39%) in low-F-cell
(average
I .38%) in high-F-cell
Family
Studies
ofHigh-F-Cell
Of the 48 high-F-cell
measured
Theoretic
by alkali
ranged
from 0. 1 7% to 0.80%
subjects
and 0.63% to 2.28%
subjects.
Among
Low
Probands
F-Cell
in Fig 2, the F-cell
counts
gene
frequency
and
include
each
0.113
the
families
(families
were
1w, Nij
and
The 21 probands
include
seven males
ratio
was
parents
1:2.
of
Wad),
In three
three
of
generations
In 20 of the
21 families,
at least
one
the family
members
male subjects
(seven
in whom
examined.
F-cell
the
Eight
counts
of nine
mothers;
high F-cell
F-cell
both
had
parents
percentages.
Thus,
low-F-cell
From
these
inheritance
remaining
from
probably
of
high
had
in eight
and
ninth.
of
not
On
and four
four of
mothers,
also
ratio of highfather
and a
0. 14 (mean
± SD).
This value
from the theoretic
value of 0.5.
±
we may
proband
trait
high-F-cell
be
high-
(seven
probands
high F-cell
fathers,
four
results,
could
and
their mothers
true in the
The segregation
born of a low-F-cell
was 0.60
different
the
parents
fathers
the high-F-cell
and
had high F-cell
percentages.
F-cell subjects
in offspring
high-F-cell
mother
was not significantly
of both
of the
hand,
all 1 1 daughters
cases)
born of eight
married
whom
there
were nine
and two secondary
low-F-cell
the nine males
was transmitted
the fathers,
and this was also
the other
secondary
studied,
probands
conclude
F-cell
trait
that
the
is
dominant
mode
of
pairings,
those
and
the F-cell
levels
of mothers,
possibly
lyonization
in the
who
trait.
both had high F-cell
In seven mother-son
of sons were always
owing
to higher
ages
higher
of the
than
latter
females.
and
high
population
high
females
high-F-cell
extremely
3).
and
population
0.1002,
and
high
at
the
and high
with
low
high
with
with
1 ). These
low
0.0889
frequencies
for the
remained
who
Despite
studied
Between
one
was
born
this,
the actual
(Table
0.8
for
among
the 2 1 probands
males,
and 6, 4, and 3 ( I 3
There
subject
were
general
males,
(Table
counts.
Relationshiop
Color
for
0.0241,
the
combinations
high
well with the theoretical
few subjects
inheriting
are calculated
as follows:
6.5 and
and 6.5, 1.6 and 5.7 (13.8 in all)
(Fig.
F-cell
This
of I :2
of 0.1 13 should
in the
level
actual
values observed
were 6 and I (7 in all)
female
of 150).
offspring
F-cell
for females
in all)
low
be the same
(31
a frequency
low with
with
3 in all)
The
X
0. 1 13. Consequently,
0.207
of parents
21 high-F-cell
subjects
(7.3 in all) for males,
had
with
(0.1 13 in all)
high
so classified
resides
on the
the high-F-cell
should
males,
high-F-cell
gene
frequencies;
females.
and
in the male/female
ratio
in the previous
section.
in various
0.0128
(0.21
High
F-cell trait
character,
observed,
female
be born
married
0.1002,
exceptional
of parents
who
values
calculations,
both
agreed
even though
1).
High-F-Cell
Trait
and
Blindness
Fifty-one
for
Five daughters
born of parents
counts can be homozygous
for this
actually
dominant
theoretically
who
and
X-linked.
that
male
following
Of all
high-F-cell
cases)
with
Both
percentages.
the high
a dominant
correlation
was also observed
in the 21 probands
described
X-linked
Female
and
frequency
of high-F-cell
females
would
be
+ 2 x 0.113 x 0.887,or0.213,a
figure which
x 0.113
of the
With
of high-F-cell
expected
probands
had a high F-cell percentage,
a dominant
transmission.
Exceptionally,
in family
parents
of the female
proband
had low F-cell
the
indicating
Ki, both
the
agrees
(high-F-cell
subjects)
of these
and 14 females;
male/female
studied.
families
percentage.
and
Population
Born ofParents
in the general
as the incidence
F-cell
ofMale
in General
Counts
could be studied
in both parents
of 21; these subjects
were
defined
as the probands.
Their
pedigrees
are shown
in Fig 3,
individuals’s
ofFrequencies
Subjects
If the gene encoding
chromosome
and has
Subjects
subjects
Analysis
High-F-Cell
ET AL
F cells,
color-blind
and
seven
adult
male
( 1 3.7%)
subjects
proved
were
to
be
examined
high-F-cell
subjects.
This level was similar
to the incidence
in the general
male population.
Two individuals,
Ha 11-I 1 (deuteranopia)
and
family,
F-cell
Yo
II-3
(deuteranopia),
as shown
trait were
among
them
in Fig 4. Transmission
quite compatible
with
were
studied
patterns
X-linked
for
of highdominant
:t#{149}1,1,..
Ni;.
Sh
0.
: ;i
.
5’.’,”
Fig 3.
subjects).
Pedigrees
of 21
probands
(high-F-cell
Number below each symbol is percentage of F cells. Subjects with high F-cell counts
(a4.4%)
(U. #{149})
Arrows indicate probands. Only
family
members
recorded.
whose
F cells could
be studied
are
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X-LINKED
DOMINANT
CONTROL
OF F-CELLS IN ADULTS
Table
1 . Theoretic
and Observed
1857
Frequencies
of High-F-Cell
Combinations
Offspring
of High and Low
F-Cell
of Both
Theoretic
Level and Genotype
F-Cell
Offspring
Father
(High)
(Low)
Male
[XY]
Sexes
of Parents
in All
Observed
Frequency
Among
Population
Mother
Born
Counts
Among
2 1 Individuals
Frequency
Among
2 1 Probands
(High)
[(XFX
+
XXF)/2
+
XFXF]
0.1002
6.5
6
0
0
0
0.8
1
[xY]
(Low)
(Low)
[XV]
[XX]
(High)
(High)
[(XFX + XX)/2
[X9Y]
+
(High)
(Low)
[XFY]
[XX]
(High)
(Low)
(High)
Female
[XV]
[(XFX + XXF)/2
(Low)
(Low)
[XV]
[Xx]
0.0128
xFxFJ
0(0.1130)’
0(7.3)
0.1002
+ XFXF]
0(7)’
6
6.5
[XFX]
[XFXF]
Values
with
are shown
low-F-cell
(High)
(High)
[X9Y]
[XFX + XXF + xFxFl
(High)
(Low)
[XFY]
[XX]
related
gene
and
to X and V chromosome
high-F-cell
0. 1002 (0. 1 1 3 x 0.887).
0.2132).
a
0
gene,
0.0889(0.2132)’
genotype.
respectively.
Low and high,
Values
among
subjects
population
among
are:
Male or female
can be obtained
as follows:
X and XF, X chromosome
(0.887
6.5
=
x 0.887),
2 1 (0. 1002)/(0.
XX or
XXF
1 1 30
+
through
in Ki in Fig 3.
three
generations
in these
two
counts).
pedi-
As for the
pedigrees,
in
high-F-cell
with both
male
subjects
family
Ha
maternally
coupling
related
of
color
in the
blindness
two
and
trait was observed
in seven male subjects
(three
and four with neither),
and repulsion
in one male
blind
but
coupling
with
low
occurred
with
one
F-cell
with
male
one
(color
counts),
male
blind
whereas
(having
but
with
in family
both)
low
Thus,
among
males
in two
families,
eight
couplings
and two repulsions
were
observed.
A daughter
(II1-3)
family
Ha, having
both traits,
was born of a consanguineous
marriage
of a color-blind
high-F-cell
father
(11-4)
and
grees.
repulsion
of F cells.
XY 0. 1 1 3, XX 0.7868
in total.
case shown
inheritance
Yo
low and high numbers
3(14)’
etc.
tExceptional
(color
with
4
5.7(13.8)’
XV 0.887,
2 1 individuals
i
1.6
0.0241
0.0 i 28 (0. 1 1 3 x 0. 1 1 3). Values
XFXF
0
and
F-cell
in
a
high-F-cell
mother
(11-5).
She can be considered
gous for the color-blindness
gene, but the genotype
high-F-cell
gene cannot
be determined.
Linkage
analyses
were performed
by the Id-score
homozyfor the
between
trait.
genes
for
color
blindness
and
high-F-cell
method
In
Ha.
‘
:‘
‘
69456’
I-1
8
‘E
Fig 4.
Family pedigrees in which both color blindness (deuteranopia)
and high-F-cell trait (F-cell counts 4.4%) were found. Arrows
indicate probands. Presence of both color blindness and high-F-cell trait (. ),
presence of color blindness only ( ). presence of
high-F-cell trait only ( . ). normal color vision and low number of F cells ( E , e ). #{149}
Not examined for color blindness or F cells. Number
below each symbol is age of individuals at the time of family survey. Numbers in parentheses
are F-cell percentages.
Yo 111-3. aged 9 years,
is not
conclusive
for
the
trait.3’
From www.bloodjournal.org by guest on June 16, 2017. For personal use only.
MIYOSHI
1858
family
Ha,
nuclear
families
the
total
(z,
two genes
indicated
no close
maximum
lod score
tive
on
evidence
score
X
from
2.05,
=
0
linkage.
1.16,
=
0
of
probands’
a linkage
family
two
0.10)
=
informative
suggested
In
Combining
chromosome.25
(z,
analyses
0.01)
=
Yo, the
pedigrees,
showed
of
score
the
for linkage.
Percentage
Compared
For
healthy
With
F-cell
assessment
same
in Other
amount
of persistent
F cells by indirect
measured
(r
at
.96)
=
range,
as shown
with
intervals
the
among
around
7% in both
F-cell
adults
were
the literature.92#{176}22
the
Japanese
Bimodal
Distribution
With Various
F-Cell
The
frequency
F-cell
levels
same
The
and 20.7%
dominant
slightly,
high-F-cell
in
to date
in
with
groups,
the
various
low-
and
in the Results
section.
We
to define
the high-F-cell
group
for
1 1 .3% of males
in an X-linked
around
4.4%
the
two
levels
accounted
groups
adults
achieved
our results
were
other
researchers
subgroups
without
greatly
high-F-cell
subjects
value
gene
The
high
for
The
F-cells
among
patterns
showed
of parents
with
close correlation
(Table
1 ).
the probands
in
classified
may
be expected
values
than
the
mode
high-F-cell
of
by the combination
X-chromosome
inactivation
the distribution
of HPFH
to show
that
of HPFH
determine
on
of HPFH,
expression
with
high and low numbers
of F cells also
with those
theoretically
expected
If lyonization
influences
population
X-linked
dominant
of male and female
frequencies
subjects
number
in the
an
supports
in
subjects
the occurrence
wider
variance
males.
However,
in both
sexes
of lyonization
with
the
in
lower
available
is not
sufficient
in this
trait
to
or its
lack.
Thus,
the dominantly
inherited
and X-linked
trait and occurrence
of color blindness
in families
is of interest.
The
vision were recently
gene loci
precisely
score
from
family
Ha
score
from
the
evidence
Further
two
may
for variations
clarified.27’28
indicate
families
other
X-linked
locus
of this
marker
HPFH
genes
a possible
linkage,
showed
trait
color
are
high-F-cell
Ha and Yo
in human
color
Although
the Id
combined
for linkage of high-F-cell
studies
for linkage with
the
no definite
with color blindness.
blindness
as well as
necessary
to search
for the
gene.
to show
that is, the more subjects
Previous
studies
concerning
results
obtained
obtained
may
by number
have failed
in the distribution
because
ofSwiss-Type
mostly
by HbF
of F cells.
to distinguish
they used
mixed
conHowthe
sam-
HPFHs
in the Literature
A review of population
HPFHs
in the literature
and family
indicates
described
incidence
the Swiss-type
HPFH
in terms
form. The incidence
of Swiss-type
HPFH
is indeed
and inheritance
studies
that
on Swiss-type
the presently
of
HPFH reported
to date ranges from 1% to 3% in the general
population.”9
The incidence
was estimated
by setting
the
upper
limit
of HbF
in normal
HbF
content),
subjects
amount
I 5%.
levels
as ours
for high
the sex-different
at a high
HbF
of F cells
subjects
or 0.7%
of the high-F-cell
in the studies
of Wood
to levels similar
to the
For
arbitrarily
point
(ie, 4.4%
the proportions
of high-F-cell
cut-off
point
adults
if the cut-off
level.9’#{176}’22However,
is set at the same
have been considered
a continuous
skewed
distribution:
studied,
the higher
the level.I2Ias
distribution
overlap,
of the results.
in normal
female
of the
section.
parents
both had
the phenotypical
parents
or a result
of gene
mutation
in the
A good compatibility
of the observed
frequency
of
Review
distinct
our interpretation
HbF
levels
of females
and the trait inherited
fashion.
We can vary the cutpoint
where
altering
and
Results
Adults
high-F-cell
groups as described
used F-cell percentage
4.4%
group.
described
of individuals
two
study
a
used, our values
are
et a120; a HbF
(AD)
F-cell
percentage
of
as those
distribution
revealed
A
in the
expression
the
mean
in the
months.
of HbF
of incomplete
females
values
obtained
are
researchers,
proba-
ranges
ofHealthy
Levels
values
of the present
absolute
various
The
in
F-cell
percentage
content
within
techniques
by Wood
to an
studies.
percentage
of several
by the results
studies.20’2’
Although
necessarily
the same
HbF in
immuno-
were within
5% of the
obtained
in the initial
in 20 individuals
bly because
of the different
similar
to those
described
content
of 1 .0% corresponds
tent;
ever,
of F-cell
repeatedly,
well
as
as described
high-F-cell
female
whose
(Fig 3) may have been
one of
proband.
expected
inheritance.
Countries
result
was previously
obtained.2’
a good correlation
with HbF(AD)
given
not
values
in Our Relsults
variations
scored
correlated
persons
similar
shows
Reported
The
samples,
means.
Content
of a small
we examined
staining.
same
other
Those
detection
adults,
fluorescent
the
and HbF
pedigrees
exceptional
F-cell
levels
result
no defini-
DISCUSSION
F-Cell
only
low
ET AL
and
of
HbF
et al2#{176}
and Rutland
et al26
levels we report,
ie, around
frequencies
of HPFH,
the values
or HbF
subjects,
calculated
by setting
the
at our level, were 14.7% in males and 19.4% in
from
individuals
of different
ages,
the more
aged
of
whom
exhibited
considerably
reduced
HbF
levels.26
These
in the data of Fujiki
et al and 8.6% in males
and
1 7.8% in females
in the data of Rutland
et al.26
Since
Marti
first reported
Swiss-type
HPFH,9
the genetic
mixed samples
with overlapping
inheritance
ples
may
not be ideal
distributions
for distinguishing
that may occur
rates
with
age.26
More
than 90% of our
obtained
from normal
adults
aged <40 years
may
have
X-Linked
made
the detection
Dominant
of subgroups
Inheritance
ofHigh-F-Cell
at
subgroups
different
samples
of age,
were
which
feasible.
females
mode
nation
to
X-linked
was
concluded
dominant
first
inheritance
from
the
of the high-F-cell
inheritance
patterns
of the
Swiss-type
ible with
Marti’s
Group
of this
have
group
inherited
in the
so.
In
trait
of inheritance
literature
HPFH
X-linked
familial
cases,9
the
the
familial
been
suspected
describing
but
of seven
high
HbF
the
undetermined.’-2’
pedigrees
male
subjects
trait
from
exact
Exami-
of families
revealed
that many pedigrees
dominant
inheritance.
For
inherited
it from
has
has remained
who
their
their mothers
and the seventh
cases of high-F-cell
subjects
with
are compatexample,
in
appeared
parents,
six
probably
reported
did
by
From www.bloodjournal.org by guest on June 16, 2017. For personal use only.
X-LINKED
DOMINANT
CONTROL
Zago et al,2’ the high-F-cell
through
their high-F-cell
bly
in the
eighth
case
OF F-CELLS
males
mothers
of eight
IN ADULTS
had the trait
in seven cases
cases
1859
transmitted
and proba-
through
two
years.35
This
childhood
an X-linked
high-F-cell
dominant
or the
HbS
trait
were
ofthe
ofthe
examined.’#{176}”3”6
the
For
F-cell
(normal)
individuals,
of F-cell
included
out
levels
ofFitting
trait
with
the genetics
and
showed
condition,
although
incidence
in the
high
pattern
in human
Hb
than
chromosome
similar
situation,
switches in human
the
classes
were
a portion
able
it was
dominant
phenotypic
controlling
formation
on some
to work
difficult,”2’
population
provided
gene(s)
hyper-IgM
Other
and
show
(recessive)
far higher
whether
determine
HPFHs
is also
gene(s)
chromosome
expression
regulatory
opmental
aspect,
modest
grade
or
of HbF.
influenced
by
we observed
of Ig
to be
and
HbF
in some
and SD of a normal
the whole data (n
of the highest
class
from
again
distribution
normal
78 classes),
one by one.
=
n
as n was
78 to n
=
further
distribution
function
44 (Fc
=
at this
that would
estimated
We
that
5.50),
=
We
the data
gradually
then
therefore
minimum
fit the
1, -- ,n) on the
square
(MRSQ)
first by using
=
then by eliminating
Thus,
the MRSQ
lessened.
to
of
point
increased
adopted
the
as representing
main group
of the population.
The mean
and SD were
2.208
and 0.702.
Because
the 99.8%
confidence
interval
of
this normal
distribution
extended
from Fc = 0 to Fc = 4.4%,
48 cases
the
outliers
of 300 whose
to the main
these
“high
48 cases
group.”
cient,
a distribution
Fcs were
group
belong
Because
>4.4%
may
at a risk <0.1%.
to
another
data
could
be considered
We conclude
that
which we call the
group
for the
function
high
group
were
insuffi-
not be determined.
ACKNOWLEDGMENT
We are greatly
cases,
aged
School
indebted
of Medicine,
with
and
to Dr
to the devel-
tute
of Radiological
high-F-cell
children
of the F cell (% Fc) appeared
normal
curve and a minor
group
data
of cumulative
distribution
(Fi)
(i
least-square
basis. The mean
residual
sum
was calculated.
We repeated
this procedure,
in such
regulatory
regard
another
healthy
Group
the
other
a trans-acting
With
distribution
a main
of
be of interest
high
in cooperation,
to Main
nondeletion5’6
It would
of the
determinants.
in some
the
decreased
evidence
of the
the developmental
agammaglobulinemia#{176}’3’
levels
on X chromosome
cis-acting
the
inheritance.
immunodeficiency.32
forms
of heterocellular8’33’34
HPFHs
is
I 1 , namely,
the X chromosome.
In a
gene
loci responsible
for developmental
immunoglobulin
(Ig) classes
should
reside
in X-linked
to
We
X chromosome,
whereas
genes
for production
are on chromosome
I 4. This has been shown
on
true
of HbF.
of X-linked
HPFH
but represents
of this
Our results
also
presence
of regulatory
switch
of HPFH
levels
mean
distribu-
Swiss-type
higher
its
transmission
on the bimodal
Distribution
higher
values,
we sought
a normal
distribution
best explain
the main body of the population.
defined
adult
high-F-cell
separate
from
the lowadults.
a Normal
Population
be composed
based
in healthy
in our definition
of this
Study
first time,
our results
as a genetic
subgroup
individuals
tion
Present
to show
APPENDIX
Algorithm
Because
Implications
also appears
to three
The possibility
of X-linked
dominant
transmission was also suggested
in some but not all other families
suspected
ofSwiss-type
HPFH in which linkages to thalassegenerations.
mia
state
control.36
from
state
of
grees.
4 to
12
School
Norikazu
We
also
to Dr Toshiro
Kanagawa)
Yasuda
(Division
Sciences,
thank
Dr
of Medicine,
Sato
(Kitasato
for statistical
of Genetics,
Chiba)
Yasuo
Insti-
analyses
(University
for helpful
of the data
National
for genetic
Natori
Tokushima)
University,
analyses
of pedi-
of Tokushima,
discussions.
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EJBM,
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of
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A
and
Weatherall
in
IA,
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of haemoglobin
A2
L, Boyer ML,
Di,
Clegg
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From www.bloodjournal.org by guest on June 16, 2017. For personal use only.
1988 72: 1854-1860
X-linked dominant control of F-cells in normal adult life: characterization of
the Swiss type as hereditary persistence of fetal hemoglobin regulated
dominantly by gene(s) on X chromosome
K Miyoshi, Y Kaneto, H Kawai, H Ohchi, S Niki, K Hasegawa, A Shirakami and T Yamano
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