CBG Santiago: a novel CBG mutation.
BACKGROUND
Corticosteroid-binding globulin (CBG; SERPIN A6) gene mutations are rare; only four mutations have been described, often in association with fatigue and chronic pain, albeit with incomplete penetrance.


METHODS
We report a kindred with a novel SERPINA6 mutation. The proband, a 9-yr-old male, had excessive postexertional fatigue, weakness, and migraine.


RESULTS
Investigations revealed low morning and ACTH-stimulated peak cortisol levels. SERPIN A6 sequencing detected a novel exon 2 single base deletion (c.13delC) leading to a frameshift generating a stop codon within the signal peptide coding region (p.Leu5CysfsX26) and 50% reduced CBG levels in heterozygotes. The patient's father and two sisters share the mutation. Symptom expression within the family may have been modified by a polymorphic CBG allele (c.735G>T). Exogenous hydrocortisone had no effect on the fatigue.


CONCLUSIONS
This report documents the fifth CBG gene mutation in humans and the second causing major effects on CBG levels. Individuals with low CBG levels may be misdiagnosed as having secondary hypocortisolism. The association with fatigue and idiopathic pain is again noted and may relate to altered stress system function. Variability of the phenotype may relate to other genetic variations of the CBG gene or environmental factors.
Endocrine and Metabolic Unit, Royal Adelaide Hospital, North Terrace, Adelaide 5000, South Australia, Australia. David.Torpy@health.sa.gov.au
D J
DJ
Torpy
B Ardesjö
BA
Lundgren
J T
JT
Ho
J G
JG
Lewis
H S
HS
Scott
V
V
Mericq
D000595:Amino Acid Sequence; D001483:Base Sequence; D002648:Child; D002677:Chile; D004252:DNA Mutational Analysis; D005221:Fatigue / Q000150:complications / Q000235:genetics; D006801:Humans; D008297:Male; D008881:Migraine Disorders / Q000150:complications / Q000235:genetics; D018908:Muscle Weakness / Q000150:complications / Q000235:genetics; D020125:Mutation, Missense; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide; D014156:Transcortin / Q000235:genetics*
C534935:SERPINA6 protein, human; D014156:Transcortin