Human sex hormone–binding globulin variants associated with hyperandrogenism and ovarian dysfunction
Kevin N. Hogeveen, … , Benoît Soudan, Geoffrey L. Hammond
Kevin N. Hogeveen, … , Benoît Soudan, Geoffrey L. Hammond
Published April 1, 2002
Citation Information: J Clin Invest. 2002;109(7):973-981. https://doi.org/10.1172/JCI14060.
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Article Endocrinology

Human sex hormone–binding globulin variants associated with hyperandrogenism and ovarian dysfunction

Abstract

The access of testosterone and estradiol to target tissues is regulated by sex hormone–binding globulin (SHBG) in human blood. Serum SHBG levels are low in patients with hyperandrogenism, especially in association with polycystic ovarian syndrome (PCOS) and in individuals at risk for diabetes and heart disease. Here, we identify SHBG coding region variations from a compound heterozygous patient who presented with severe hyperandrogenism during pregnancy. Serum SHBG levels in this patient measured 2 years after her pregnancy were exceptionally low, and her non–protein-bound testosterone concentrations greatly exceeded the normal reference range. A single-nucleotide polymorphism within the proband’s maternally derived SHBG allele encodes a missense mutation, P156L, which allows for normal steroid ligand binding but causes abnormal glycosylation and inefficient secretion of SHBG. This polymorphism was identified in four other patients with either PCOS, ioiopathic hirsutism, or ovarian failure. The proband’s paternal SHBG allele carries a single-nucleotide deletion within exon 8, producing a reading-frame shift within the codon for E326 and a premature termination codon. CHO cells transfected with a SHBG cDNA carrying this mutation fail to secrete the predicted truncated form of SHBG. To our knowledge, these are the first examples of human SHBG variants linked to hyperandrogenism and ovarian dysfunction.

Authors

Kevin N. Hogeveen, Patrice Cousin, Michel Pugeat, Didier Dewailly, Benoît Soudan, Geoffrey L. Hammond

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Figure 1

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Identification of SHBG sequence variations in a DNA sample from the prob...
Identification of SHBG sequence variations in a DNA sample from the proband. (a) Schematic representation of the 4.3-kb genomic fragment comprising the human SHBG transcription unit showing the transcription start site (arrow), and the positions of exons in relation to the two overlapping amplicons generated for sequence analysis. (b) The sequence variations in exons 4 and 8 within separate SHBG alleles from the proband are compared with the consensus SHBG sequences on the proband’s other allele. The SNP in exon 4 is designated as P1, while the single-nucleotide deletion in exon 8 is designated as P2. Separate alleles were identified based on the presence or absence of P1 within the exon 4 sequences of the overlapping 5′ and 3′ amplicons shown in a. Arrows indicate the positions of sequence variations.