SERPINA6 – Corticosteroid-binding Globulin Deficiency

SERPINA6 encodes corticosteroid-binding globulin (CBG), the principal plasma carrier for cortisol. Germline variants that reduce CBG levels or affinity disrupt cortisol transport and bioavailability, manifesting clinically as CBG deficiency with hypotension, hypo-/hypertension, and predominant muscle fatigue. Variable inheritance patterns—including autosomal recessive null homozygotes and de novo heterozygous missense alleles—point to haploinsufficiency as a key mechanism in human disease.

Genetic evidence includes 3 unrelated probands with pathogenic SERPINA6 variants: a de novo c.1165G>A (p.Asp389Asn) causing severe fatigue in a normotensive patient ([PMID:17245537]), a homozygous c.776G>T (p.Gly237Val) null allele in a 26-year-old woman and her two affected siblings ([PMID:20610591]), and a compound heterozygous case with p.Trp393Ser and p.Asp367Asn presenting undetectable binding activity ([PMID:22948765]). Segregation was observed in the two siblings of the Gly237Val homozygote family ([PMID:20610591]). These variants comprise both loss-of-function and missense changes that abolish steroid binding, supporting an autosomal recessive inheritance model.

In vitro functional assays confirm that specific substitutions—Leu115His and Arg307Gly—reduce cortisol-binding affinity by >2- to 4-fold in transfected cell systems ([PMID:1504007]; [PMID:16702435]). A murine Cbg null model recapitulates fatigue and immune defects, consistent with human phenotypes ([PMID:19643166]). Concordant expression and ligand-binding studies across species bolster a haploinsufficiency mechanism.

No studies convincingly refute the role of SERPINA6 in CBG deficiency, and experimental evidence complements genetic findings. Although additional rare variants have been catalogued, case numbers remain limited.

Collectively, SERPINA6 variants that impair CBG production or cortisol affinity underlie corticosteroid-binding globulin deficiency, with clinical utility in diagnosis of unexplained fatigue syndromes and hormone-binding disorders.

Key Take-home: Pathogenic SERPINA6 alleles causing CBG haploinsufficiency define an autosomal recessive disorder of cortisol transport, critical for targeted diagnostic evaluation.

References

• Journal of neural transmission (Vienna, Austria : 1996) • 2007 • Haploinsufficiency of the SERPINA6 gene is associated with severe muscle fatigue: A de novo mutation in corticosteroid-binding globulin deficiency. PMID:17245537
• The Journal of clinical endocrinology and metabolism • 2010 • Novel corticosteroid-binding globulin variant that lacks steroid binding activity. PMID:20610591
• The Journal of clinical endocrinology and metabolism • 2012 • Two different corticosteroid-binding globulin variants that lack cortisol-binding activity in a greek woman. PMID:22948765
• The Journal of steroid biochemistry and molecular biology • 1992 • A Leu----His substitution at residue 93 in human corticosteroid binding globulin results in reduced affinity for cortisol. PMID:1504007
• Genetics • 2006 • Functional implication of an Arg307Gly substitution in corticosteroid-binding globulin, a candidate gene for a quantitative trait locus associated with cortisol variability and obesity in pig. PMID:16702435
• Molecular and cellular endocrinology • 2010 • Corticosteroid-binding globulin: the clinical significance of altered levels and heritable mutations. PMID:19643166

Evidence Based Scoring (AI generated)