PMID- 10634411
OWN - NLM
STAT- MEDLINE
DCOM- 20000203
LR  - 20131121
IS  - 0021-972X (Print)
IS  - 0021-972X (Linking)
VI  - 85
IP  - 1
DP  - 2000 Jan
TI  - Novel human corticosteroid-binding globulin variant with low cortisol-binding
      affinity.
PG  - 361-7
AB  - Corticosteroid-binding globulin (CBG) is the plasma transport protein that
      regulates the access of glucocorticoid hormones to target cells. Genetic
      deficiencies of CBG are rare, and only a single human CBG variant (Trancortin
      Leuven) has been related so far to decreased cortisol-binding affinity. We report
      here on a 43-yr-old woman, referred for chronic asthenia and hypotension, with
      repeatedly low morning serum cortisol levels (22-61 nmol/L; normal range, 204-546
      nmol/L), normal plasma ACTH levels (38-49 pg/mL; normal, <50 pg/mL), and normal
      urinary cortisol (10-76 nmol/24 h; normal range, 10-105 nmol/24 h). An increased 
      percent-free (dialysable fraction) serum cortisol (8.7-9.7%, normal range,
      2.9-3.9%) suggested abnormal CBG binding activity. Indeed, she had a low serum
      CBG concentration (24 mg/L vs. 44+/-6 mg/L in normal women), and the affinity of 
      her CBG for cortisol was decreased (association constant, Ka = 0.12 L/nmol vs.
      0.82+/-0.29 L/nmol). In her immediate family members, the serum CBG concentration
      and cortisol-binding activity were normal in her husband, but the four living
      children had slightly lower serum CBG concentrations than the reference ranges
      for their pre- and postpubertal status. Measurements of cortisol distribution in 
      undiluted serum indicated that an increase in the percentage of nonprotein-bound 
      cortisol offsets the low cortisol levels to give approximately normal
      concentrations of free cortisol in serum. Direct sequencing of PCR-amplified
      exons encoding CBG revealed that the proband was homozygous for a polymorphism
      (GAC-AAC) in the codon for residue 367, which results in a Asp367-->Asn
      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.
FAU - Emptoz-Bonneton, A
AU  - Emptoz-Bonneton A
AD  - Hospices Civils de Lyon, Laboratoire de la Clinique Endocrinologique, Hopital de 
      l'Antiquaille, Lyon, France.
FAU - Cousin, P
AU  - Cousin P
FAU - Seguchi, K
AU  - Seguchi K
FAU - Avvakumov, G V
AU  - Avvakumov GV
FAU - Bully, C
AU  - Bully C
FAU - Hammond, G L
AU  - Hammond GL
FAU - Pugeat, M
AU  - Pugeat M
LA  - eng
PT  - Case Reports
PT  - Journal Article
PL  - United States
TA  - J Clin Endocrinol Metab
JT  - The Journal of clinical endocrinology and metabolism
JID - 0375362
RN  - 0 (DNA Primers)
RN  - 0 (DNA, Complementary)
RN  - 0 (Hormones)
RN  - 9010-38-2 (Transcortin)
RN  - WI4X0X7BPJ (Hydrocortisone)
SB  - IM
MH  - Adrenal Cortex Diseases/genetics/psychology
MH  - Adult
MH  - Amino Acid Substitution/genetics
MH  - Blotting, Western
MH  - DNA Primers
MH  - DNA, Complementary/biosynthesis/genetics
MH  - Female
MH  - Hormones/blood
MH  - Humans
MH  - Hydrocortisone/blood/*metabolism
MH  - Mutagenesis
MH  - Polymorphism, Genetic/genetics
MH  - Polymorphism, Restriction Fragment Length
MH  - Protein Binding
MH  - Transcortin/*chemistry/genetics/metabolism
EDAT- 2000/01/14 00:00
MHDA- 2000/01/14 00:01
CRDT- 2000/01/14 00:00
PHST- 2000/01/14 00:00 [pubmed]
PHST- 2000/01/14 00:01 [medline]
PHST- 2000/01/14 00:00 [entrez]
AID - 10.1210/jcem.85.1.6315 [doi]
PST - ppublish
SO  - J Clin Endocrinol Metab. 2000 Jan;85(1):361-7. doi: 10.1210/jcem.85.1.6315.