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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Identification of a single-nucleotide deletion (P2) in exon 8 of the hum...
Identification of a single-nucleotide deletion (P2) in exon 8 of the human SHBG in DNA samples from the proband and her family members. (a) P2 disrupts a BbsI site in the consensus SHBG sequence and causes a frameshift in codon E326 that introduces a novel sequence followed by a stop codon. A common SNP (P3) also disrupts this BbsI site, as well as a HinfI site that is preserved in P2. The solid oval indicates the position of an additional N-glycosylation site introduced by the D327N substitution caused by P3. (b) Ethidium bromide–stained polyacrylamide electrophoresis gel of PCR-amplified exon 8 sequences digested with either BbsI or HinfI. Approximately half of the PCR products from the proband and from her father and sister are resistant to BbsI digestion but are completely digested with HinfI. By contrast, patients who are homozygous (patients TD and BE) or heterozygous (patient CV) for P3 show either complete or partial resistance to BbsI and HinfI digestion, respectively. The PCR products (sizes, in bp, shown on the left) from patients in which the consensus exon 8 sequence is present (patients DC, CS, and GS) are digested completely by BbsI and HinfI. Genotypes are: homozygous consensus sequence (+/+), heterozygous carriers of the single-nucleotide deletion (P2) in exon 8 (+/P2), homozygous carriers of P3 (P3/P3), and heterozygous carriers of P3 (+/P3).