CBG Santiago: a novel CBG mutation.

Area of Science:

• Endocrinology
• Human Genetics

Background:

• Corticosteroid-binding globulin (CBG; SERPIN A6) gene mutations are rare, with only four previously described.
• These mutations are often associated with fatigue and chronic pain, though penetrance is incomplete.

Observation:

• A kindred presented with a novel SERPINA6 mutation in a 9-year-old male experiencing excessive postexertional fatigue, weakness, and migraine.
• Investigations revealed low morning and ACTH-stimulated peak cortisol levels.

Findings:

• A novel exon 2 single base deletion (c.13delC) in SERPIN A6 was detected, causing a frameshift and premature stop codon.
• This mutation resulted in 50% reduced CBG levels in heterozygotes and was shared by the patient's father and two sisters.
• Symptom variability may be influenced by a polymorphic CBG allele (c.735G>T).

Implications:

• This represents the fifth identified human CBG gene mutation and the second significantly impacting CBG levels.
• Individuals with low CBG may be misdiagnosed with secondary hypocortisolism.
• The association with fatigue and pain suggests a link to altered stress system function, with phenotype variability possibly due to other genetic or environmental factors.