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.
View: Text | PDF
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

×

Figure 2

Options: View larger image (or click on image) Download as PowerPoint
Identification of an SNP (P1) that disrupts an MspI site within the exon...
Identification of an SNP (P1) that disrupts an MspI site within the exon 4/intron 4 boundary of human SHBG in DNA samples from the proband and female patients with reproductive disorders. Ethidium bromide–stained polyacrylamide electrophoresis gel of PCR-amplified exon 4 sequences digested with MspI. The enzyme fails to completely digest PCR products from the variant allele in samples from the proband and three other patients (patients CV, DC, and CS). By contrast, PCR products (sizes, in bp, shown on the left) from the proband’s father and sister and three patients (patients TD, BE, and GS) are digested completely by MspI. Genotypes are: homozygous consensus sequence (+/+) and heterozygous carriers of the MspI SNP (+/P1).