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Original Studies |
Hospices Civils de Lyon, Laboratoire de la Clinique Endocrinologique (A.E.-B., P.C., M.P.) and Département d’Endocrinologie (C.B.), Hôpital de l’Antiquaille, 69321 Lyon Cedex 05; INSERM U 329, Hôpital Debrousse, 69005 Lyon, France; and Departments of Obstetrics and Gynecology and Parmacology and Toxicology, University of Western Ontario and London Regional Cancer Centre (K.S., G.V.A., G.L.H.), N6A 4L6 London, Ontario, Canada
Address correspondence and requests for reprints to: Michel Pugeat, Laboratoire de la Clinique Endocrinologique, Hôpital de l’Antiquaille, 1 rue de l’Antiquaille, 69321 Lyon Cedex, France. E-mail: laboendo{at}cismsun.univ-lyon1.fr
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Abstract |
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 Top Abstract IntroductionSubjects and MethodsResultsDiscussionReferences |
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AAC) in the codon for residue 367,
which results in a Asp367Asn substitution. Her children
were heterozygous for this polymorphism. When this nucleotide change
was introduced into a normal human CBG complementary DNA, for
expression in Chinese hamster ovary cells, Scatchard analysis
demonstrated that the Asn367 substitution reduced the
affinity of human CBG for cortisol by approximately 4-fold
(Ka = 0.15 L/nmol), as compared to normal
recombinant CBG (Ka = 0.66 L/nmol). These results
suggest that Asp367 is an important determinant of CBG
steroid-binding activity and that normal negative regulation of the
hypothalamic-pituitary-adrenal axis is maintained by relatively normal
serum-free cortisol concentrations, despite a marked reduction in the
steroid-binding affinity of this novel human CBG variant, which we have
designated as CBG-Lyon. |
Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Plasma CBG is produced by hepatocytes (4, 5). After a progressive decline during puberty, CBG levels in human blood remain stable throughout adult life (6), but individual levels are determined, in part, by inheritance (7, 8). The human CBG gene (cbg) has been mapped to chromosome 14q32.1 (9) and comprises five exons distributed over approximately 19 kilobases (kb), with the complete coding sequence for CBG spanning exons 2–5 (10). Genetic deficiencies of CBG have been reported in humans (8, 11, 12, 13, 14, 15), and two studies have related a low affinity for cortisol to a single polymorphism in human cbg (15, 16). In the present study, we report the clinical and endocrine profiles of a patient with a decreased serum CBG concentration and low affinity for cortisol, and we have shown that these abnormalities are related to a genetic polymorphism that results in a novel amino acid substitution in the CBG polypeptide.
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Subjects and Methods |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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The proband is a 43-yr-old woman of northwest African origin who was referred for chronic asthenia, depressive mood, and low blood pressure, suggesting adrenal deficiency. She also has a history of duodenal ulcer. Her mother died at 56 yr of age from gastric cancer, and her father died at 73 yr of age from posthepatitis cirrhosis. Two of her sisters (twins) died at age 6 months from an undetermined cause, and her four brothers and three living sisters are in good health. Her husband is a first cousin and had no pathological records. The patient had five pregnancies, one of which produced twins: a girl who died 20 min after cesarean delivery and a boy who died accidentally at 3 yr of age. Her four living children (all girls, aged, respectively, 21, 11, 8, and 6 yr) were in good health, but the eldest (daughter 1) was overweight.
On physical examination, the patient had a body mass index of 33 kg/m2, and a blood pressure of 100/70 mm Hg with no postural hypotension. She had normal basal and postprandial glucose and insulin levels, but hypokaliemia at 3.4 mmol/L (normal range, 3.5–4.5 mmol/L) with low urinary potassium (29 mmol/24 h; normal range, 40–75 mmol/24 h). Albumin was slightly decreased at 36.3 g/L (normal range, 36.5–51.5 g/L), and she was anemic with 10.4 g hemoglobin/dL and normal mean corpuscular volume (90 µm3). On abdominal tomodensitometry x-ray scans, there were two hepatic angiomas (34 and 12 mm in diameter) and normal adrenals and kidneys.
Reagents
Oligonucleotide primers were synthesized by Eurogentech (Seraing, Belgium) or the Molecular Biology Core Facility of the Medical Research Council of Canada Group in Fetal and Neonatal Health and Development (London, Ontario, Canada). Taq DNA polymerase was obtained from ATGC Biotechnologie (Noisy le Grand, France), and TaqI enzyme was from Boehringer (Mannheim, Germany). Unless otherwise stated, [1,2-3H]cortisol (55–72 Ci/mmol) from DuPont Canada, Inc. (Mississauga, Ontario, Canada) and unlabeled cortisol from Steraloids, Inc. (Wilton, NH) were used without further purification. Polybrene was purchased from Aldrich Chemical Co., Inc. (Milwaukee, WI). Culture medium, antibiotics, Geneticin (G418), FBS, and trypsin-ethylenediaminetetraacetate were obtained from Life Technologies, Inc. Canada (Burlington, Ontario, Canada). Other chemicals were from Merck & Co., Inc.(Darmstadt, Germany).
Serum cortisol and CBG measurements
Serum and urinary cortisol was measured by RIA after extraction and chromatographic separation (17), and the free cortisol fraction in diluted (1:5) serum was measured initially by equilibrium dialysis using freshly purified [3H]cortisol as the tracer (18). Serum CBG concentrations were measured by RIA, as described (19). The binding capacity of CBG and its affinity for cortisol were measured at 4 C by a solid-phase assay using Concanavalin A-Sepharose (20).
Centrifugal ultrafiltration dialysis was also used to determine the
percentage of nonprotein-bound (NPB) cortisol in undiluted serum
samples (21). In brief, aliquots (450 µL) of serum were incubated at
37 C for 30 min with freshly purified
[3H]cortisol (1.5 pmol) and 
15,000 dpm
[14C]-glucose. Duplicate 200-µL aliquots of
the incubated serum were then transferred to ultrafiltration vials and
centrifuged at 3000 x g for 1 h at 37 C. The
percentage of NPB cortisol was calculated by dividing the ratio of
[3H]cortisol to
[14C]glucose in the ultrafiltrate by the
corresponding ratio in the serum retained by the dialysis membrane. The
distribution of [3H]cortisol between the
different serum components was calculated from measurements of the
percentage of NPB cortisol in untreated and heat-treated serum (60 C
for 1 h to eliminate CBG-binding activity), as described
previously (22).
Other serum hormone and protein measurements
Plasma ACTH was measured using an enzyme-linked immunosorbent assay kit (CIS-Bio International, Gif-sur-Yvette, France). The proband was also given ACTH and CRH tests as follows: for the ACTH test, 0.25 mg 1–24 ACTH (Synacthen; Ciba-Geigy, Rueil-Malmaison, France) was injected iv and blood samples were drawn 1 min before and 60 min after the injection; for the CRH test, 1 µg/kg body weight of human CRH (Ferring Pharmaceuticals Ltd., Gentilly, France) was injected iv and blood samples were drawn 1 min before, and 30 and 60 min after the injection.
Serum testosterone and androstenedione concentrations were measured by
RIA after extraction and chromatographic separation, whereas
dehydroepiandrosterone (DHEA) and
DHEA-sulfate were measured by direct RIA methods, as
described previously (23). Aldosterone was measured by RIA
(Immunotech, Marseille, France) and renin by an
immunoradiometric assay obtained from Pasteur Sanofi Pharmaceuticals, Inc. Diagnostics (Marnes la Coquette, France).
Free T4 was measured by an immunoradiometric assay (Ortho
Clinical Diagnosis, Roissy, France), and TSH was measured by a RIA
(Abbott, Rungis, France). T4-binding globulin was measured
by RIA (CIS-Bio International, Gif-sur-Yvette, France),
whereas transferrin and 
1-antitrypsin
(1-AT) were measured by immuno-nephelometry (Boehring
Diagnostics, Rueil-Malmaison, France).
Western blotting
Serum was diluted (1:100) in phosphate-buffered saline (PBS; pH 7.4), mixed with SDS-loading buffer, heated to 100 C for 2 min, and subjected to SDS-PAGE with 4% and 7.5% acrylamide in the stacking and resolving gels, respectively. Proteins were transferred electrophoretically onto a nitrocellulose membrane (Amersham Pharmacia Biotech, Les Ulis, France). After blocking nonspecific sites with nonfat milk in Tris-buffered saline for 1 h, the membrane was incubated overnight with a rabbit-derived polyclonal antiserum against human CBG (13) diluted (1:500) in Tris-buffered saline. Immunoreactive proteins were detected by a horseradish peroxydase-labeled second antibody detection system (ECL-detection kit; Amersham Pharmacia Biotech), according to the manufacturer’s protocol.
DNA sequencing
Informed written consent was obtained from the proband and her
husband. Genomic DNA from all family members was extracted from white
blood cells by phenol-chloroform. The human cbg exons 2–5
were amplified by PCR using intron-specific oligonucleotide primers
described previously (15). In brief, the PCR was performed in 100 µL
containing genomic DNA (50 ng), primers (100 pmol each), dNTP (25 nmol
each), and Taq DNA polymerase (1 U). Reaction mixtures were
overlaid with mineral oil and subjected to 30 cycles of amplification,
as described in Table 1
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-35S]deoxy-ATP (ICN Biomedicals, Inc. Orsay, France). The reaction products were run on 5%
polyacrylamide gels, which were subsequently subjected to
autoradiography (BioMax film, Eastman Kodak Co.,
Rochester, NY) for 12–72 h. Restriction fragment length polymorphism (RFLP) analysis
Human cbg exon 5 was amplified by PCR using the following oligonucleotide primers: 5'-AGCTGTGCTGCAACTCAATG forward and 5'-TTTCTGTGGGATCCCTGGTT reverse, as described above with an annealing temperature of 53 C. The PCR products were digested by TaqI as: 10 IU TaqI in 24 µL of enzyme buffer was added to 25 µL of PCR products and incubated overnight at 65 C; then, 10 µL of each sample was added to 2 µL of electrophoresis loading buffer and subjected to 6% PAGE. The gel was stained with ethidium bromide, and DNA fragments were identified under ultraviolet light.
Mutagenesis and expression of CBG complementary DNAs (cDNAs)
A cDNA encoding the human CBG precursor polypeptide (24) was
inserted into the pSelect vector (Promega Corp., Madison,
WI) and mutated, according to instructions provided by Promega Corp., with a single-stranded complementary oligonucleotide
designed to mutate the codon for Asp367
(GACAAC). The resulting cDNA for CBG-Asn367
was sequenced to ensure that only the targeted mutation had occured.
The mutant and unmodified CBG cDNAs were reinserted within the
HindIII-XbaI sites of pRc/CMV
(Invitrogen, San Diego, CA) for expression in mammalian
cells.
The cDNA expression constructs for wild-type human CBG and
CBG-Asn367 were transfected into Chinese hamster
ovary (CHO) cells using the Polybrene-dimethylsulfoxide technique (25).
In brief, exponentially growing CHO cells were incubated overnight in
-MEM containing 10% FBS (MEM-FBS) in 10-cm diameter dishes. The
medium was replaced with 2.5 mL MEM-FBS containing plasmid DNA (1
µg), followed by 5 µL Polybrene (10 mg/mL sterile water). The
dishes were agitated several times during a 6-h incubation at 37 C,
after which the DNA-Polybrene mixture was removed, and 5 mL 30%
dimethylsulfoxide in MEM-FBS were added for 4 min. The cells were then
washed with PBS and cultured in MEM-FBS for 48 h before the
addition of G418 (2 mg/mL) for selection of neomycin-resistant
cells. After 7 days, cells were washed twice in PBS and then cultured
in MEM-FBS. Two days before the cell culture medium was harvested for
CBG assays, the MEM-FBS was replaced by serum-free medium.
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Results |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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The results in Table 2 show that
serum cortisol levels in the proband were very low despite ACTH levels
in the normal range. Urinary cortisol, measured three times, was 10,
73, and 76 nmol/24 h and was within the normal range (10–105 nmol/24
h). Although the percent-free cortisol in the proband’s serum was
increased (8.7–9.7% vs. 2.9–3.9% in normal control
women), her free cortisol concentration was at the lower limit of the
normal range (Table 2), and this is suggestive of an abnormal CBG
binding activity for cortisol. Indeed, the patient’s serum
concentration of immunoreactive CBG (24 mg/L; see Table 2) and CBG
binding capacity for cortisol (273 nmol/L) were both lower than normal
reference ranges, i.e. 44 ± 6 mg/L and 865 ± 315
nmol/L, respectively (6). Serial dilutions of the proband’s serum
(1:500–1:4000 in PBS + 10% BSA) were also tested in an RIA for CBG,
and the displacement curve generated was parallel with the human CBG
standards, as well as serial dilutions of serum from a normal subject.
Hence, the immunoreactivity of the variant CBG is normal, and this
validates its measurement by the RIA. The CBG affinity for cortisol
(Fig. 1) was lower in the proband
(association constant, Ka = 0.12 L/nmol) than in normal
control women (Ka = 0.82 ± 0.29 L/nmol) or her
husband (0.87 L/nmol). Among the proband’s family members, her husband
had a normal serum CBG concentration (40 mg/L), whereas the four
children had slightly decreased serum CBG concentrations (28–40 mg/L)
when compared to the age-related reference range (6).
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) demonstrated that cortisol in the
proband’s serum is mainly bound to albumin (42.8% vs. a
mean of 7.4% for two controls) and that the NPB cortisol is greatly
increased (28.1% vs 3.5%). However, despite the reduced
concentration and cortisol-binding affinity of the proband’s CBG,
approximately one third of the cortisol in her serum is capable of
binding to her CBG (29.1% vs. 89.0% in normal controls).
It is also of interest that the serum distribution of cortisol is not
completely normal in two of the proband’s daughters, and this probably
reflects the presence of one variant CBG allele in these individuals
(Fig. 2A). The actual concentrations of cortisol that are NPB, CBG
bound, and albumin bound were also calculated from the distribution
data and the serum concentrations of cortisol in the proband and two of
her daughters (Fig. 2B). This illustrates the fact that both the
amounts of NPB and albumin-bound cortisol are relatively normal in the
proband, but that the amount of cortisol bound to CBG is remarkably
low.
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In the proband, serum cortisol increased from 50 to 253 nmol/L 60 min after ACTH injection. Serum ACTH also increased from 36 to 69 pg/mL, and serum cortisol rose from 58 to 94 nmol/L 30 min after CRH injection. These data indicate that the hypotalamo-pituitary-adrenal axis in the proband functions normally.
Serum testosterone (0.6 nmol/L), androstenedione (2.9 nmol/L), DHEA (17.9 nmol/L), and DHEA sulfate (2 µmol/L) were within the reference ranges of premenopausal women. Aldosterone increased from 77 pmol/L in decubitus to 234 pmol/L in the upright posture (40–85 and 275–415 pmol/L, respectively, in normal controls), with plasma renin concentration also increasing normally from 1.9 pg/mL in decubitus to 5.1 pg/mL in the upright posture (2.6–4 and 6–8.4 pg/mL, respectively, in normal controls).
Free T4 at 20 pmol/L, TSH at 1.37 mUI/L, and TBG
at 22.6 mg/L were within the normal range (10–23 pmol/L, 0.12–3.8
mUI/L, and 12–28 mg/L, respectively). Transferrin at 2.2 g/L (1.9–3.7
g/L) and 1-AT at 1.25 g/L (1–1.8 g/L) were
normal.
Western blotting
When examined by Western blotting, heat-denatured CBG in the
proband’s serum migrates during SDS-PAGE with an apparent molecular
size similar to that of CBG in a normal serum sample, and this was also
true for CBG in the serum from each member of her family (Fig. 3).
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Amplification and analysis of CBG coding sequences in genomic DNA
from the proband revealed a homozygous point mutation in exon 5, within
the codon for residue Asp367 (GACAAC), which
results in an Asn substitution. Her four children are heterozygous
carriers of this genetic defect, and it is not present in her
husband’s DNA (Fig. 4).
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GCG), which results in a Ser224Ala
substitution that has no effect on steroid binding (15). The four
children were also heterozygous for this polymorphism (data not shown).
No other variations from the most common human cbg coding
sequence (15, 24) were observed in the proband or her family
members. RFLP analysis
As anticipated from the mutation observed in the proband’s
cbg exon 5 sequence, PCR products of her cbg exon
5 (209 bp) are resistant to digestion by TaqI. By contrast,
TaqI digestion of the corresponding PCR products of her
husband’s DNA resulted in two bands (120 and 89 bp) that are
indicative of a normal sequence. As also predicted, when the same
experimental conditions were applied to DNA samples from the proband’s
four children TaqI digestion lead to three fragments (209,
120, and 89 bp) that are indicative of the presence of one normal and
one abnormal allele (Fig. 5). This simple
assay is, therefore, a convenient means of detecting this type of CBG
polymorphism.
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The cortisol-binding affinity of human
CBG-Asn367 produced by CHO cells
(Ka = 0.15 L/nmol) is lower than the cortisol-binding
affinity of wild-type human CBG (Ka = 0.66 L/nmol)
produced in this way (Fig. 6) and is
close to that observed for CBG in proband’s serum (see above).
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Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Among these reports are patients in whom a reduced plasma CBG
concentration, with no apparent change in its steroid-binding activity,
seems to be inherited in a Mendelian fashion (8). In these patients, it
is likely that only one CBG allele is expressed, but the genetic basis
of this inherited trait has never been determined. There have also been
several reports of CBG variants that bind cortisol with approximately
one third of the affinity associated with normal CBG (11, 13, 14). Two
of the variants have been characterized at the molecular level and are
clearly the result of a common genetic polymorphism that causes a
Leu93His substitution at residue 93 in the CBG
molecule (15, 16).
There are two other reports in which total deficiencies of CBG in human subjects have been reported (12, 14). In both cases, the detection of CBG in blood samples has relied solely on steroid-binding capacity measurements that are sensitive to changes in the binding affinity of the protein (26), and neither report has been substantiated by immunochemical detection of the protein in the blood, or a genetic analysis. Although we cannot be certain, these variants might be very similar to the variant (CBG-Lyon) characterized in this report because we used the steroid-binding capacity assay described by Roitman et al. (12) to analyze CBG-Lyon in the serum from the proband and failed to detect any steroid-binding activity (data not shown). At the present time, it is, therefore, unlikely that individuals exist with a complete CBG lack, and this supports the conclusion of an early study that attempted to identify such individuals in a very extensive immunochemical screening study (27).
When compared to the reduction in steroid-binding affinity associated
with the Leu93His substitution found in
Transcortin-Leuven, the Asp367Asn substitution
in CBG-Lyon has a greater effect on reducing the affinity of CBG for
cortisol. The specificity of this effect was confirmed by producing and
studying the steroid-binding properties of a recombinant human CBG
variant with only an Asp367Asn substitution.
When this information is compared with what is known about the
structure of CBG and related serine proteinase inhibitors (serpins)
with hormone-binding activities, such as
T4-binding globulin, it confirms the prediction
that the carboxyl-terminal regions of these molecules contain residues
that are important features of their ligand-binding domains (28). Based
on the domain structures proposed in the latter report, the amino-acid
substitution in CBG-Lyon may also be in close proximity to
Trp371, which has been located within the CBG
steroid-binding site, as demonstrated by photoaffinity-labeling
experiments (29) and site-directed mutagenesis (30).
The reason why the serum concentration of CBG is also reduced in the
proband and some of her children is unclear, but the plasma albumin
level in the proband was also slightly below the normal range. No other
mutation exists in the coding sequence of the proband’s CBG gene, but
the Asp367Asn substitution might also reduce
the hepatic secretion or clearance of the variant CBG in these
subjects. In this regard, genes encoding CBG and
1-AT are part of a cluster of serpin genes
located on human chromosome 14q32.1 (31), and there is 43% sequence
identity between CBG and 1-AT (24). It has
been shown that carriers of the
Z1-AT mutant have
1-AT deficiency because of impaired liver
secretion of the mutant protein (32). This Z variant has a
single amino acid substitution (Glu342Lys),
which is also in the carboxyl-terminal region of the protein, and it is
possible that other structural differences in this region of serpins,
such as the one that exists in CBG-Lyon, could have generalized effects
on their secretion.
When the reduced steroid-binding activity of CBG-Lyon, and its effects on the serum distribution of cortisol, are considered in relation to the reduced levels of total cortisol in serum, it is apparent that the concentration of free cortisol is only minimally affected. This accounts for the apparently normal urinary cortisol excretion and the normal circadian ACTH variations with normal ACTH response to CRH infusion, which all suggest that the hypotalamo-pituitary-adrenal axis is unimpaired. It also accounts for the lack of hypo- or hypercortisism in the proband, who revealed no signs of corticosteroid deficiency in stress situations, such as deliveries, surgery, or acute viral infection. Although her blood pressure was low, potassium metabolism and aldosterone secretion were normal. However, it cannot be excluded that a more rapid clearance of cortisol might have a deleterious effect in CBG-deficient individuals during stress-induced cortisol secretion (33). It should also be appreciated that the amounts of cortisol bound to CBG in the proband are considerably lower than in normal women or in her daughters who express one allele for a CBG with normal cortisol-binding affinity, as demonstrated by Scatchard analysis (Emptoz-Bonneton, A., unpublished data), and perhaps it is actually this abnormality in CBG-bound cortisol that contributes to her symptoms, which are also very similar to those reported for another CBG variant (14) that remains to be characterized at the molecular level.
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Acknowledgments |
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Footnotes |
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Received August 27, 1999.
Accepted October 14, 1999.
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References |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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His
substitution at residue 93 in human corticosteroid-binding globulin
results in reduced affinity for cortisol. J Steroid Biochem Mol Biol. 42:671–676.[CrossRef][Medline]
1-proteinase inhibitor and thyroxine-binding globulin properties. J Biol Chem. 274:15046–15051.
6 derivatives of cortisol, corticosterone, and progesterone as
unsubstituted photoreagents. Biochemistry. 33:8969–8981.[CrossRef][Medline]
1-antitrypsin and corticosteroid-binding globulin genes on
chromosome 14q32.1. Mamm Genome. 8:913–916.
1-antitrypsin. Nature. 298:329–334.
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) and her husband (
). The number of binding
sites contained in 100 µL plasma are indicated by the x intercept.
The CBG affinity for cortisol is indicated by the slope of the line.
), one
daughter (center), heterozygous, and her father
(proband’s husband) (left), normal.
