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From www.bloodjournal.org by guest on August 13, 2017. For personal use only.
Homozygous
Hemoglobin
Knossos
fl-Thalassemia
By
Hb
(
Knossos
hemoglobin
ties1121
F. Baklouti,
27
We
a
Algeria.
but
the
1 9-year-old
is
Knossos.
syndrome,
including
enlargement
cases.
is
from
to
soon
and
“normal
Hb
with a “high
gene, generates
in
afterwards
state,
the
Hb
families
French
heterozyas the
from
Knossos
of Hb
is flanked
by
was
northeast
mutation
with
A25 has
In
causes
suggested
origin.
We present
have $-thalassemia
that
at
the
Sebia
by
was
of Betke
after
alkali
chains
a
in
two first
intermedia
system
trile
Knossos was previously
described.5
Hematological
abnormalities
were discovered
during
evaluation
for an unrelated
orthopedic
problem.
Mild cutaneous
pallor was noted. The spleen extended
1 cm
below the costal margin.
Radiological
evaluation
of the skeleton
revealed abnormalities
of the right humerus
and the left femur, a CS
hemivertebra,
and a L5 spina occulta,
but the characteristic
stigmata of thalassemia
were absent. The red cell indices were RBC,
l0’2/L,
Knossos.
splenic
10,1
and target
Anisocytosis
The
Hb,
sister
(11.4)
g/dL;
MCV,
52 fL (serum
iron
4.5 mol).
She is 8 years
enlargement
propositus
is also
a homozygote
old and asymptomatic.
were
present.
Neither
However,
she
had
for
icterus
Hb
nor
mm
was
The
peptides
of I .50 mL/min.’2’3
using
Oxygen
Borsook.’4
differential
conditions
were separated
lose filters,’6
5.7),
of acetoni-
with
a flow
of abnormal
amino
out
acid analyzer.
In
essentially
according
curves
on
a LKB
composition
leukocytes
presence
recommended
and
gradient
(pH
dissociation
from
to 1 5 big) in the
ments
in
rate
peptide
were
vitro
to
performed
spectrophotometer.
obtained
using
to
or
(HPLC)
Mass)
an increasing
acid
and
chromatography
acetate
Amino
chroma-
by fingerprinting”
Milford,
lII3 was performed
in a Biotronic
globin
chain
synthesis
was carried
and
Knossos.
analyzed
liquid
ofammonium
proce-
PAGE7
crA and fl”#{176}”
to aminoethylation
(Waters,
Sweden),
mol/L
F by the
by ion exchange
subjected
column
Hb
by Triton-urea
A and/or
separated
by
of Triton
at 570 nm. Hb A2
and
were
analyzed
in the presence
were studied
Hb
fl-chain
were
chains
as described’5
of restriction
by
the
manufacturers.
DNA
agarose gels, transferred
in 0.8%
hybridized
with
and
32P-labeled
was
endonucleases,
to
probes.
frag-
nitrocellu-
Four
probes
to recognize
the seven polymorphic
sites described
by
Orkin et al’7: (a) a 1.3-(kb) Bam HI/EcoRl
gene fragment
in pBR
328; (b) a 0.8-kb Pst l/EcoRl
A’y IVS II in PSP 65; (c) a 1 .7-kb
‘fl
Bgl
II/Xba
I fragment
in pBR
328;
and
(d) a 0.95-kb
Barn
Hl/EcoRI
fi IVS II in pBR 322.
used
RESULTS
In the
untransfused
1, Fig
focusing
became
propositus
2a and
c). Hb
slightly
more
more apparent
(11.1),
A was
cathodically
when IEF
Hb
replaced
was
A2 was
absent
by a component
(Fig 2a). This change
carried
out in agarose
moderate
1 ). The parents
and two brothers
who were studied
show a hematological
picture
characteristic
of heterozygous
Hb
Knossos”3’4 (Table 1).
Methods.
Hemoglobin
analysis
was performed
by isoelectric
focusing (IEF) according
to Basset et al,6 or on agarose gels provided
anemia
(P,,:38
is character-
Gels were scanned
were
(Bromma,
in 0.01
(Table
cells were present.
of the
of urea.7
C18
were
Hb
Globin
high-performance
is apparently
x
Hb
‘-thalassemia.
mutations
(PAGE)
of
Bondapak
(I0
5.14
affinity
microchromatofocusing8
digestion.”
digested
in which
determination.
homozygotes
in a Hemoscan
families
is
containing
Inc.
precipitation
reverse-phase
METHODS
Algerian
oxygen
these
et al.9 -y-Chains
from
tryptic
the
least
using
Case report.
The propositus
(III,
Fig IB),
is a 19-year-old
Algerian
who has lived in France since 1982. He was born in Rabta,
80-km west of Setif in northeast
Algeria.
His parents
are not
consanguineous,
but both originate
from Rabta. The present family
two
synthesis
cells
I.
& Stratton,
and 8 mol/L
assayed
was
to the
$-chain
homozygous
gel electrophoresis
DNA
unrelated
carrying
Hb A,
for
polyacrylamide
Lingrel
AND
has
haplotype
by Grune
of
Whole
low
also
DNA
tography.’#{176} The
#{176}-thalassemia.
MATERIALS
chromosome
1986
reduction
a dramatically
by the
of
and J. Delaunay
a:2.76).
propositus
ized
dure
Indies.35
a #{244}#{176}-thalassemic gene,
have
The
X-I00
trait.”2
Knossos
West
The
The
S
J. Godet,
(a/non
Knossos
Variety
number
fl.thalassemia
the
Hb
have
anemia.
in the
reticulocytes.
Hg).
A2” f.-thalassemia
trait and, when
associated
Hb A2” fl-thalassemia
trait or a Lepore
fusion
a picture
of3-thalassemia
jj1.3.5
The
persons
of mediterranean
homozygous
persons
who
associated
who
Ser) in the
recognized
Crete,’
in two
or absence
gene
Ala -‘
recently
pro-
intermedia
increase
from
from
low
Knouos
an
atypical
in a family
heterozygous
Algerians
hypochromic
and
in a family
The
A New
#{246}#{176}-Thalassemia
M. Aubry,
pronounced
northeast
a $-thalassemia
microcytic.
abnormality
Algeria
other
has
(fl27 (B9)
has
been
identified
discovered
the
homozygous
spleen.
B KNOSSOS
gous
state
First
first
originally
of
proper-
Ser):
-k
With
D. Peyramond,
discovered
$-thalassemic
man
He
of the
underlying
is a recently
with
Ala
Associated
L. Morl#{233}, P. Laselve,
Ser)
-‘
unrelated
hemoglobin
H
Ala
endowed
present
positus.
Intermedia
E. Dorlac,
(B9)
variant
(a2 fl227(B9)
(Table
From
the Groupe
de Recherches
M#{234}decine; D#{233}partement
Herriot;
and
Croix-Rousse,
Service
des
Maladies
Lyon. France;
et Appliqu#{233}e. Villeurbanne,
Supported
.11
A
.2
44yr[
J
B
I
,ft
2
l9yr
llyr
NCS
Grant
J37yr
J
8yr
Recherche,
and grant
No.
A1034661
Recherche
Scientijique.
Cedex
Fig I .
Pedigree
gene. Ages of family
of the family
studied:
members
are shown.
Blood, Vol 67, No 4 (April), 1986:
pp 957-96
D,
$
gene;
#{149}.
©
Infectieuses,
Edouard
Hbpital
de Biologie
Universit#{233} Claude
the
Minist#{232}re de
Oct. 22, /984; accepted
requests
to Dr F. Baklouti,
Rouge,
Facult#{233}de
Hbpital
de
Ia
G#{233}n#{233}rale
France.
the
from
Globule
lyr
by
Rouge,
Clinique.
and Laboratoire
84L0686
Submitted
Address
II
#{149}l #{149}I:1
#{149}E
l4yr
No.
in part
sur le Globule
de Biochimie
from
Bernard
Lyon
I ‘Industrie
the Centre
et
National
Oct. 28, /985.
Groupe
de Recherches
Facult#{233}de M#{233}decine, Grange-Blanche
69373
I,
de Ia
de Ia
sur
Ic
Lyon
08. France.
I 986 by Grune
& Stratton,
Inc.
0006-4971/86/6704-00/8$03.00/0.
1
957
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BAKLOUTI
958
Table
(Parameters)
Index
RBC(x
10’2/L)
Parameters
I. 1
1.2
,. II. 1
11.3
11.4
11.5
5.84
4.75
5.32
4.86
5.24
5.07
16.0
11.7
10.1
11.1
9.5
11.8
MCV(fL)
79.5
74.4
58.4
70.2
58.3
71.5
27.3
24.7
19.1
22.8
18.1
23.4
(pg)
Reticulocytes
Serum
(%)
4.80
iron (zmol/L)
-
HbA2,
(%)
a/nona
P50. mm Hg
2,3-DPG
(mol/g
Hb)
Determined
by scanning
Normal
values
2.69%
§Normal
values
(n
2b).
presence
of
fl-chain
variant
=
±
1 5):
P
studies
2.24
0.00
-
-
3).
normal
chromatography
that
the
peptide
abnormal
the
place
of
abnormal
2.39
-
2.62
13.88
The reason
2.43
39.7
38.0
2.52
13.04
for the elevation
of the reticulocyte
count
in I. 1 is unknown.
gels.
1 .57
±
mm
ascertained
homozygous
were
an
= 2.69
out
was
depressed
(38
Fingerprints
4a),
of
but
existence
of
F was
slightly
Hb
in the
propositus.
Hg)
the
and
The
a
in
abnormal
residue
(Table
2).
/3-chain
-
+
-
persons
and
as
IEF
Knossos
on polyacrylamide
revealed
on agarose
gels
since
variations
it can
maternal
or slightly
showed
heterozygotes
substantial
that
the
brothers
precentage
the
#{176}.y
levels
were
be
assumed
that
reasonably
chromosomes
suggest that 11.3
(Table
gel analysis
failed
gel. Electrophoresis
remarkably
of
(11.3
decreased
was
Knossos
percentages
(/327(B9)
origin.’8
heterozygous
Conventional
in
Knossos
of mediterranean
the two
normal
Hb
Hb
globin gene cluster
carried
haplotype
+ ), the most
frequently
encountered
A2 was
chain
data
hemoglobin
non-a
Hb
of Triton-urea
liquid
These
The
among
detect
(HPLC)
profiles
allowed
recognition
of an
(Fig 4b). Amino
acid analysis
ascertained
peptide
was T3, with a senine
residue
in
alanine
the abnormal
Ala -#{247} Ser).
I (+ -
11.5),
1 .90 mol/gHb.
±
In the parents
ii remained
high-performance
1 2.83
haplotype
2.76).
=
=
identified
a
A similar
picture
(Table
I).
(a/non
mm
0. 1 1 ; 2.3-DPG
±
gel in the
the
state.
carried
increased
(Fig
i
Hg;
in a polyacrylamide
of /3-chains
(Fig
appeared
4.72
26.2
2.76
propositus.
27.20
=
X- I 00
in the
dramatically
normal
1.60
36.5
0.00
35.5
-
38.1
1.35
of polyacrylamide-urea-Triton
0.62%
(n - 352).
Electrophoresis
Triton
synthesis
P50 was
2.30
21.1
-
-
1.44
with a G,., percentage
of 21.1%.
in the second
homozygote
(11.4)
Further
95.3
1.50
by chromatofocusing.
tDete’mined
increased
was found
.
-
37.1
1.69
14.12
7
20.8
1.94
2.56
II. 1 and Il.4 are homozygotes;
(Fig
0.81
20.0
33.5
i:i HiIl
-
2.80
16.5
96.6
-
41.1
1 .0
15
37.6
0.38
()t
6.00
6
37.5
HbF(%)
G-y
1 .80
18
HbKnossos(%)
/3k/fl(%)t
vitro
and Hemoglobin
Hb(g/dL)
MCH
gels
1 . Red Cell Indices
ET AL
and
1).
to
of the
homogeneous,
found.
the
but
However,
paternal
and
1 1 are identical,
the Gsy
and 11.5 have inherited
the
#{247}
F
M
P”
+
F
Fig 2.
Isoelectric
electrophoresis;
anhydrase.
focusing
and
(B) IEF on agarose
electrophoretic
gel;
analyses:
(C) electrophoresis
M
I
P
P. propositus;
on polyacrylamide
C
F. father;
M. mother;
gel in the
C. control;
presence
(A) IEF on polyacrylamide
of urea-Triton
X-100.7
CA.
gel
carbonic
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HOMOZYGOUS
HEMOGLOBIN
959
KNOSSOS
S
Hb02.
1oo
:
a
“
100
(--)
Fig 3.
father;
normal
Oxygen
(-)
dissociation
propositus.
chromosome
a/non-a
ratios
and
0
150
P02,mmHg
) control
curves:
(.
I 1 from
their
father.
In the parents,
the
were
found
to be
P
.
.
(i
2.56);
the
moderately
increased.
DISCUSSION
described
We
the
third
To our knowledge,
first
recorded
types
associated
suggests
homozygous
with
that
sons
of
contrast
Algerian
the
cases.
and
similarity
in blacks
among
per-
origin,
and
in Creole
side
of the
Mediterranean
carrying
this
Algeria.
the
gene,4
families
that
hemoglobin
northeastern
would
/3-thalassemia
The
basin
noting
in detecting
All families
described
because
/3-thalassemia,
Hb
of
Lepore,
tion
of Hb
Knossos.
The
study
of a homozygote.
normal
serum
iron
low
part
Hb
Knossos
to date
that
other
or Hb
present
region
frequency
screening
display
/3-chain
Hb
The
present
presence
mutation
persons
recognized
of Hb
Knossos
in
origin.
different
a distinct
but
Hb
screening
homozygotes
confirms
data
/3 gene
among
#{244}#{176}-Thalassemiahas
populations.2#{176}23
#{244}#{176}-thalassemia
gene
the hematological
by
of a microcytosis
decreased
Hb A2
of a #{244}#{176}-thalassemia
gene in cis to the
previously
suspected”4
or demonstrated5
of mediterranean
described
cases,22
study
Knossos
demonstra-
was
a mild
form
of a-thalassemia,
should
be considered
and the appropriate
should
be used.
technique
IN
abnormalities,
5, facilitated
The association
and an inconstantly
In
must
are not consistent
be involved
with
been
homozygous
since
a homozygous
Fig 4.
Peptide
high-performance
and the propositus
Hb Knossos.
No large
deletion
was found
to be associated
with the #{246}#{176}-thalassemia
gene cis to the /3”#{176}”
gene.5 Similar-
ly, previous
tion
studies
defects.23’24
These two cases
on b#{176}-globingenes
of
homozygous
LMI.
of
be empha-
suggests
Knossos
of
of Algeria.
must
family
Sc
in
in independent
scale
in this
first
families
a 200-km2
a large
patients
discovered
the
apparently
Knossos
Algerian
of homozygotes
require
were
usually
the
Given
sized.
with
from
intermedia
difficulty
three
originate
the detection
probably
hemoglobin
the
as
people
is not flanked
by a 6#{176}-thalassemia gene and is associated
another
haplotype.’9
Although
it is not known
on which
it is worth
I
in
that
with
arose,
B
of haplo-
mediterranean
found
Knosare the
mutations
is involved
southern
to the mutation
Hb
her sister
the Algerian
chromosome
and
with
and
The
the Greek’8
same
northern
family
the propositus
have
Hb
shown
Knossos
nondelemay
be
analysis:
(A) tryptic
liquid chromatography
(bottom).
digestion
profiles
fingerprints;
of a control
(B)
(top)
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BAKLOUTI
960
Table
2.
Amino
Amino
Acid
Composition
acid
Normal
Asx
of the fiT3#{176}’#{176}
Peptide
Values
1.70
GIx
2
2.30
Ser
0
0.92
Gly
3
2.92
Ala
1
Val
3
Traces
3.00
Leu
1
Arg
1
to
reflect
Fib
E
mutations
that
disease.
Both
also
Hb
sis (2.76
may
evolve
the case
whom
for
we
into
a more
serious
the patient
with
recently
described.5
clinical
Hb
Knossos
Homozygous
the clinical
salient
E
been
Hb Lepore
Hb Knossos
found
in the
are
the
the
a t5#{176}-thalassemia gene
with
propositus
synthesis,
and
cases of homozyThis
genotype
intermedia.
The
marked
affinity
association
and
the
reduced
of
of the
DNA
haplotype
I.
ACKNOWLEDGMENT
condition
as has
features
imbalance
in globin
chain
Hb Knossos
for oxygen,
gene
sever&’3
association.29
most
I-lb
may
Paradoxi-
is less
0.85
mRNA
which
severity.
association
0.77
this
and
reduce
/3-thalassemia-/3’#{176}
present
report
describes
the two first
Knossos
in an Algerian
family.
produces
the phenotype
of /3-thalassemia
and
syndrome
E disease,
in globin
chain syntherefs. 26-28).
Decreased
Hb
to abnormal
Perhaps
should
Hb
The
enlarged.
was
the
than
imbalance
=
8)) (see
than the /3thalassemia/3E
anemia
spleen
affinity
cally,
child (11.4) has significant
aneThe propositus
had comparable
the
V
oxygen
splicing.’8’25
The 8-year-old
mia but is asymptomatic.
but
severe
pronounced
1.43 to 2.30 (n
gous
Knossos
contribute
to be more
a more
reflect
2
compared
appears
$T31”
ET AL
We thank
Drs
samples,
analyses,
and
P. Brugiroux
and
J.L.
Chiron
for providing
Mrs C. Vianey-Liaud
for performing
Mrs M. Anzilutti
for the preparation
blood
us with
the amino acid
of the manu-
script.
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Ph, Loukopoulos
D, Loutradi-Anagnostou
A, Komis G:
‘Silent’
fi-thalassaemia
caused
by a ‘silent’ /3-chain
mutant:
The
pathogenesis
of a syndrome
of thalassaemia
intermedia.
Br J Haematol
51:577,
1982
F, Fessas Ph, Loukopoulos
D, Blouquit Y,
G, Sellaye
M, Boussiou
M, Rosa J: Structural
study of
hemoglobin
Knossos,
/327 (B9) Ala -‘
5cr. A new abnormal
hemoglobin
present as a silent /3-thalassemia.
FEBS Lett 147:247,
I982
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F, Chardin
P, Boissel JP, Beghoul
F, Labie D,
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M: Silent f3-thalassemia
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/327(B9) Ala -. 5cr in Algeria.
Hemoglobin
7:555, 1983
4. Galacteros
F, Delanoe-Garin
J, Monplaisir
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2. Arous
N, Galacteros
Komis
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Arous
Blouquit
Y, Mamalaki
A, Tulliez
M, Rosa J: Two new cases of heterozygosity
$2
27 Ala .-‘ 5cr detected
in the French
a2
Hemoglobin
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M, Goossens
J: The association
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ME,
to the
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THJ:
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in fetal haemoglobin
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Br J Haematol
44:527, 1980
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A, Dorl#{233}acE, Cloppet
H, Delaunay
J: Chromatofocusing of human
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228:177,
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Clegg
JB,
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Homozygous hemoglobin Knossos (alpha 2 beta 227(B9) Ala----Ser): a new
variety of beta+-thalassemia intermedia associated with delta degreethalassemia
F Baklouti, E Dorleac, L Morle, P Laselve, D Peyramond, M Aubry, J Godet and J Delaunay
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