CBG Santiago: A Novel CBG Mutation

Context: 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. Patient: We report a kindred with a novel SERPINA6 mutation. The proband, a 9-yr-old male...

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Bibliographic Details
Published in:The journal of clinical endocrinology and metabolism 2012-01, Vol.97 (1), p.E151-E155
Main Authors: Torpy, D. J, Lundgren, B. Ardesjö, Ho, J. T, Lewis, J. G, Scott, H. S, Mericq, V
Format: Article
Language:English
Subjects:
Amino Acid Sequence
Base Sequence
Child
Chile
DNA Mutational Analysis
Fatigue - complications
Fatigue - genetics
Humans
Male
Migraine Disorders - complications
Migraine Disorders - genetics
Muscle Weakness - complications
Muscle Weakness - genetics
Mutation, Missense
Pedigree
Polymorphism, Single Nucleotide
Transcortin - genetics
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Summary:Context: 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. Patient: We report a kindred with a novel SERPINA6 mutation. The proband, a 9-yr-old male, had excessive postexertional fatigue, weakness, and migraine. Main Outcome Measures and 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. Conclusion: 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.
ISSN:0021-972X
1945-7197
DOI:10.1210/jc.2011-2022