title: 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.affiliation: Department of Obstetrics and Gynecology, University of Western Ontario, London, Ontario, Canada.
authors.forename: Kevin N
authors.initials: KN
authors.lastname: Hogeveen
authors.forename: Patrice
authors.initials: P
authors.lastname: Cousin
authors.forename: Michel
authors.initials: M
authors.lastname: Pugeat
authors.forename: Didier
authors.initials: D
authors.lastname: Dewailly
authors.forename: Benoît
authors.initials: B
authors.lastname: Soudan
authors.forename: Geoffrey L
authors.initials: GL
authors.lastname: Hammond
mesh_terms: D000328:Adult; D000483:Alleles; D000818:Animals; D001665:Binding Sites; D016466:CHO Cells; D006224:Cricetinae; D019003:Deoxyribonuclease HpaII; D005091:Exons; D005260:Female; D017353:Gene Deletion; D015870:Gene Expression; D005820:Genetic Testing; D014644:Genetic Variation; D006801:Humans; D017588:Hyperandrogenism / Q000235:genetics*; D010053:Ovary / Q000503:physiopathology; D011085:Polycystic Ovary Syndrome / Q000235:genetics*; D011110:Polymorphism, Genetic; D011247:Pregnancy; D012738:Sex Hormone-Binding Globulin / Q000235:genetics*; D013739:Testosterone / Q000378:metabolism
chemical_list: D012738:Sex Hormone-Binding Globulin; D013739:Testosterone; D019003:Deoxyribonuclease HpaII