SHBG (sex hormone-binding globulin)
2010-11-01 Nicoletta Fortunati , Maria Graziella Catalano AffiliationLab Endocrinologia Oncologica, Dip Oncologia, AOU San Giovanni Battista & Dip Fisiopatologia Clinica, Universita di Torino, Via Genova 3, 10126 Torino, Italy
DNA/RNA
Schematic representation of SHBG gene. Exons are represented by the blue boxes.
Description
The human SHBG gene is located on the short arm of chromosome 17 (17pter-p12) and consists of eight exons.
Transcription
Two major SHBG transcripts are known, each originating from a different promoter. The variant 1, which has also been referred to as SHBG-L, encodes the longest protein (isoform 1), while the variant 2 uses an alternate in-frame splice site in the 3 coding region compared to variant 1. These two transcripts differ in their 5 sequence and in the absence of exon 7 in the latter one.
Proteins
Note
402 amino acids; 43779 Da each subunit: homodimer.
Linear structure of SHBG protein. Location of glycosylation sites is shown by red lines.
Description
SHBG is a homodimer; each monomer is constituted of 402 aa, molecular weight 43,7 kDa. The protein consists of a signal peptide (1-29 aa) and 2 laminin G-like domains (domain 1: 45-217 aa; domain 2: 224-390 aa). Each SHBG monomer has an O-linked oligosaccharide at Thr(36) and up to two N-linked oligosaccharides at Asn(380) and Asn(396).
Localisation
SHBG is secreted by liver into the blood stream and it is synthesized by testis germ cells; it also recognizes a specific binding site located on membranes of sex steroid target cells (e.g. breast, prostate).
Function
SHBG binds and carries sex steroids, regulating their biological active fraction; it also regulates sex steroid effects in target cells by direct action.
Mutations
Note
CCG-CTG; Pro-Leu156; reported in hyperandrogenism.
GAC-AAC; Asp-Asn327; reported in estrogen-dependent breast cancer.
(TAAAA)n promoter, n=6-11; n>8; reported in: polycystic ovary syndrome; CAD in postmenopausal women; reduced bone mineral density in men; metabolic syndrome.
GAC-AAC; Asp-Asn327; reported in estrogen-dependent breast cancer.
(TAAAA)n promoter, n=6-11; n>8; reported in: polycystic ovary syndrome; CAD in postmenopausal women; reduced bone mineral density in men; metabolic syndrome.
Implicated in
Entity name
Breast cancer
Note
Human serum sex hormone-binding globulin (SHBG) regulates the bioavailable fraction of circulating estradiol that is known to be a critical factor in breast cancer. In a case-controlled study within the European Prospective Investigation into Cancer and Nutrition (EPIC), SHBG levels in postmenopausal women who developed breast cancer were confirmed to be significantly lower compared with controls, while no significant difference was observed in premenopausal women.
SHBG has a direct effect in breast cancer cells; it interacts with membranes of these cells, initiates subsequently a specific intracellular pathway leading to cross-talk with the estradiol-activated pathway, finally inhibiting several effects of estradiol in breast cancer cells, e.g. cell proliferation.
The Asp327Asn polymorphism of SHBG gene is related to breast cancer risk. Cui et al. observed a significant association of the Asp327Asn polymorphism with reduced breast cancer risk and Becchis et al. reported a significantly higher frequency of the polymorphism in postmenopausal patients with ER-positive breast cancer than in ER-negative; more recently Costantino and co-workers suggested a protective role of this polymorphism since mutated SHBG is more effective than wild type protein in inhibiting estradiol-induced cell proliferation and anti-apoptosis, and this is due to the fact that D327N SHBG binds to MCF-7 cells to a greater extent than does wild type protein.
SHBG has a direct effect in breast cancer cells; it interacts with membranes of these cells, initiates subsequently a specific intracellular pathway leading to cross-talk with the estradiol-activated pathway, finally inhibiting several effects of estradiol in breast cancer cells, e.g. cell proliferation.
The Asp327Asn polymorphism of SHBG gene is related to breast cancer risk. Cui et al. observed a significant association of the Asp327Asn polymorphism with reduced breast cancer risk and Becchis et al. reported a significantly higher frequency of the polymorphism in postmenopausal patients with ER-positive breast cancer than in ER-negative; more recently Costantino and co-workers suggested a protective role of this polymorphism since mutated SHBG is more effective than wild type protein in inhibiting estradiol-induced cell proliferation and anti-apoptosis, and this is due to the fact that D327N SHBG binds to MCF-7 cells to a greater extent than does wild type protein.
Entity name
Prostate cancer
Note
Patients with prostate cancer showed lower SHBG levels than benign prostate hypertrophy patients and controls.
Alternative splicing of SHBG gene is more pronounced in LNCaP and MCF-7 cancer cell lines; at least six independent transcripts each, resulting from alternative splicing of exons 4, 5, 6, and/or 7 were described.
SHBG might be a significant multivariate predictor of lymph node invasion in patients with prostate cancer. The use of preoperative serum SHBG could help to identify patients at risk of lymph node invasion.
Alternative splicing of SHBG gene is more pronounced in LNCaP and MCF-7 cancer cell lines; at least six independent transcripts each, resulting from alternative splicing of exons 4, 5, 6, and/or 7 were described.
SHBG might be a significant multivariate predictor of lymph node invasion in patients with prostate cancer. The use of preoperative serum SHBG could help to identify patients at risk of lymph node invasion.
Entity name
Type 2 diabetes mellitus
Note
Epidemiological studies consistently show that circulating SHBG levels are lower in type 2 diabetes patients than in non-diabetic individuals.
Low circulating levels of SHBG are a strong predictor of the risk of type 2 diabetes in women and men.
Carriers of a variant allele of the SHBG single-nucleotide polymorphism (SNP) rs6259 and carriers of a rs6257 variant were associated with a risk of type 2 diabetes following their associated sex hormone-binding globulin levels.
Low circulating levels of SHBG are a strong predictor of the risk of type 2 diabetes in women and men.
Carriers of a variant allele of the SHBG single-nucleotide polymorphism (SNP) rs6259 and carriers of a rs6257 variant were associated with a risk of type 2 diabetes following their associated sex hormone-binding globulin levels.
Entity name
Insulin resistance and polycystic ovary syndrome (PCOS)
Note
SHBG concentrations are inversely associated with insulin resistance, and in turn, with the risk of type 2 diabetes.
Women with polycystic ovary syndrome (PCOS) present low SHBG levels that are negatively correlated with body mass index and waist to hip ratio, and are, furthermore, associated with insulin resistance.
Women with polycystic ovary syndrome (PCOS) present low SHBG levels that are negatively correlated with body mass index and waist to hip ratio, and are, furthermore, associated with insulin resistance.
Article Bibliography
| Pubmed ID | Last Year | Title | Authors |
|---|---|---|---|
| 18188141 | 2008 | The importance of the (TAAAA)n alleles at the SHBG gene promoter for the severity of coronary artery disease in postmenopausal women. | Alevizaki M et al |
| 19748550 | 2010 | Structural analyses of sex hormone-binding globulin reveal novel ligands and function. | Avvakumov GV et al |
| 10424400 | 1999 | The additionally glycosylated variant of human sex hormone-binding globulin (SHBG) is linked to estrogen-dependence of breast cancer. | Becchis M et al |
| 15664449 | 2005 | Sex hormone-binding globulin antagonizes the anti-apoptotic effect of estradiol in breast cancer cells. | Catalano MG et al |
| 18437557 | 2009 | Molecular mechanisms of the D327N SHBG protective role on breast cancer development after estrogen exposure. | Costantino L et al |
| 15894658 | 2005 | Association of breast cancer risk with a common functional polymorphism (Asp327Asn) in the sex hormone-binding globulin gene. | Cui Y et al |
| 19657112 | 2009 | Sex hormone-binding globulin and risk of type 2 diabetes in women and men. | Ding EL et al |
| 16926255 | 2006 | SHBG gene promoter polymorphisms in men are associated with serum sex hormone-binding globulin, androgen and androgen metabolite levels, and hip bone mineral density. | Eriksson AL et al |
| 19770023 | 2010 | Sex Hormone-Binding Globulin (SHBG), estradiol and breast cancer. | Fortunati N et al |
| 10675319 | 2000 | Crystal structure of human sex hormone-binding globulin: steroid transport by a laminin G-like domain. | Grishkovskaya I et al |
| 19921964 | 2010 | Lipoproteins, sex hormones and inflammatory markers in association with prostate cancer. | Grosman H et al |
| 11927624 | 2002 | Human sex hormone-binding globulin variants associated with hyperandrogenism and ovarian dysfunction. | Hogeveen KN et al |
| 9292933 | 1997 | Sequence and functional relationships between androgen-binding protein/sex hormone-binding globulin and its homologs protein S, Gas6, laminin, and agrin. | Joseph DR et al |
| 15900045 | 2005 | Serum sex steroids in premenopausal women and breast cancer risk within the European Prospective Investigation into Cancer and Nutrition (EPIC). | Kaaks R et al |
| 16322344 | 2005 | Postmenopausal serum androgens, oestrogens and breast cancer risk: the European prospective investigation into cancer and nutrition. | Kaaks R et al |
| 19416531 | 2009 | Human sex hormone-binding globulin gene expression- multiple promoters and complex alternative splicing. | Nakhla AM et al |
| 1315262 | 1992 | Binding of an extracellular steroid-binding globulin to membranes and soluble receptors from human breast cancer cells (MCF-7 cells). | Porto CS et al |
| 19786070 | 2010 | Sex hormone-binding globulin gene expression in the liver: drugs and the metabolic syndrome. | Pugeat M et al |
| 19698759 | 2010 | Interactions of sex hormone-binding globulin with target cells. | Rosner W et al |
| 19038425 | 2009 | Sex hormone-binding globulin: a novel marker for nodal metastases prediction in prostate cancer patients undergoing extended pelvic lymph node dissection. | Salonia A et al |
| 12235141 | 2002 | A human sex hormone-binding globulin isoform accumulates in the acrosome during spermatogenesis. | Selva DM et al |
| 6750727 | 1982 | The serum transport of steroid hormones. | Siiteri PK et al |
| 2421156 | 1986 | Steroid-protein interactions II. | Westphal U et al |
| 20690069 | 2011 | The (TAAAA)n polymorphism of the SHBG gene in men with the metabolic syndrome. | Xita N et al |
| 14671199 | 2003 | Association of the (TAAAA)n repeat polymorphism in the sex hormone-binding globulin (SHBG) gene with polycystic ovary syndrome and relation to SHBG serum levels. | Xita N et al |
| 9195154 | 1997 | Characterisation of X;17(q12;p13) translocation breakpoints in a female patient with hypomelanosis of Ito and choroid plexus papilloma. | Zajac V et al |
Other Information
Locus ID:
NCBI: 6462
MIM: 182205
HGNC: 10839
Ensembl: ENSG00000129214
Variants:
dbSNP: 6462
ClinVar: 6462
TCGA: ENSG00000129214
COSMIC: SHBG
RNA/Proteins
Expression (GTEx)
References
| Pubmed ID | Year | Title | Citations |
|---|---|---|---|
| 37605959 | 2024 | The relationship between sex hormone-binding protein and non-alcoholic fatty liver disease using Mendelian randomisation. | 1 |
| 37725912 | 2024 | Sex Hormone-Binding Globulin and Risk of Incident Dementia in Middle-Aged to Older Women: Results from the UK Biobank Cohort Study. | 1 |
| 37735050 | 2024 | Causal relationship between schizophrenia and sex hormone binding globulin: A Mendelian randomization study. | 0 |
| 38051322 | 2024 | The Association Between SHBG and Osteoporosis: A NHANES Cross-Sectional Study and A Bidirectional Mendelian Randomization. | 0 |
| 38320264 | 2024 | Longitudinal Changes in Sex Hormone Binding Globulin (SHBG) and Risk of Incident Diabetes: The Study of Women's Health Across the Nation (SWAN). | 1 |
| 38394359 | 2024 | Association of Testosterone and Sex Hormone-Binding Globulin With All-Cause and Cardiovascular Disease Mortality in Older Chinese Men. | 0 |
| 38396861 | 2024 | Sex-Hormone-Binding Globulin Gene Polymorphisms and Breast Cancer Risk in Caucasian Women of Russia. | 2 |
| 38796576 | 2024 | Blood lipid levels mediating the effects of sex hormone-binding globulin on coronary heart disease: Mendelian randomization and mediation analysis. | 0 |
| 37605959 | 2024 | The relationship between sex hormone-binding protein and non-alcoholic fatty liver disease using Mendelian randomisation. | 1 |
| 37725912 | 2024 | Sex Hormone-Binding Globulin and Risk of Incident Dementia in Middle-Aged to Older Women: Results from the UK Biobank Cohort Study. | 1 |
| 37735050 | 2024 | Causal relationship between schizophrenia and sex hormone binding globulin: A Mendelian randomization study. | 0 |
| 38051322 | 2024 | The Association Between SHBG and Osteoporosis: A NHANES Cross-Sectional Study and A Bidirectional Mendelian Randomization. | 0 |
| 38320264 | 2024 | Longitudinal Changes in Sex Hormone Binding Globulin (SHBG) and Risk of Incident Diabetes: The Study of Women's Health Across the Nation (SWAN). | 1 |
| 38394359 | 2024 | Association of Testosterone and Sex Hormone-Binding Globulin With All-Cause and Cardiovascular Disease Mortality in Older Chinese Men. | 0 |
| 38396861 | 2024 | Sex-Hormone-Binding Globulin Gene Polymorphisms and Breast Cancer Risk in Caucasian Women of Russia. | 2 |
Citation
Nicoletta Fortunati ; Maria Graziella Catalano
SHBG (sex hormone-binding globulin)
Atlas Genet Cytogenet Oncol Haematol. 2010-11-01
Online version: http://atlasgeneticsoncology.org/gene/42286/shbg-(sex-hormone-binding-globulin)
