SHBG (sex hormone-binding globulin)

2010-11-01   Nicoletta Fortunati  , Maria Graziella Catalano  

Lab Endocrinologia Oncologica, Dip Oncologia, AOU San Giovanni Battista & Dip Fisiopatologia Clinica, Universita di Torino, Via Genova 3, 10126 Torino, Italy

Identity

HGNC
SHBG
LOCATION
17p13.1
LOCUSID
6462
ALIAS
ABP,SBP,TEBG
FUSION GENES
Show Gene Fusions

DNA/RNA

Atlas Image
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.
Atlas Image
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.

Homology

Protein S, Gas6, laminin, agrin.

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.

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.
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.
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.
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.

Article Bibliography

Pubmed IDLast YearTitleAuthors
181881412008The 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
197485502010Structural analyses of sex hormone-binding globulin reveal novel ligands and function.Avvakumov GV et al
104244001999The additionally glycosylated variant of human sex hormone-binding globulin (SHBG) is linked to estrogen-dependence of breast cancer.Becchis M et al
156644492005Sex hormone-binding globulin antagonizes the anti-apoptotic effect of estradiol in breast cancer cells.Catalano MG et al
184375572009Molecular mechanisms of the D327N SHBG protective role on breast cancer development after estrogen exposure.Costantino L et al
158946582005Association of breast cancer risk with a common functional polymorphism (Asp327Asn) in the sex hormone-binding globulin gene.Cui Y et al
196571122009Sex hormone-binding globulin and risk of type 2 diabetes in women and men.Ding EL et al
169262552006SHBG 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
197700232010Sex Hormone-Binding Globulin (SHBG), estradiol and breast cancer.Fortunati N et al
106753192000Crystal structure of human sex hormone-binding globulin: steroid transport by a laminin G-like domain.Grishkovskaya I et al
199219642010Lipoproteins, sex hormones and inflammatory markers in association with prostate cancer.Grosman H et al
119276242002Human sex hormone-binding globulin variants associated with hyperandrogenism and ovarian dysfunction.Hogeveen KN et al
92929331997Sequence and functional relationships between androgen-binding protein/sex hormone-binding globulin and its homologs protein S, Gas6, laminin, and agrin.Joseph DR et al
159000452005Serum sex steroids in premenopausal women and breast cancer risk within the European Prospective Investigation into Cancer and Nutrition (EPIC).Kaaks R et al
163223442005Postmenopausal serum androgens, oestrogens and breast cancer risk: the European prospective investigation into cancer and nutrition.Kaaks R et al
194165312009Human sex hormone-binding globulin gene expression- multiple promoters and complex alternative splicing.Nakhla AM et al
13152621992Binding of an extracellular steroid-binding globulin to membranes and soluble receptors from human breast cancer cells (MCF-7 cells).Porto CS et al
197860702010Sex hormone-binding globulin gene expression in the liver: drugs and the metabolic syndrome.Pugeat M et al
196987592010Interactions of sex hormone-binding globulin with target cells.Rosner W et al
190384252009Sex hormone-binding globulin: a novel marker for nodal metastases prediction in prostate cancer patients undergoing extended pelvic lymph node dissection.Salonia A et al
122351412002A human sex hormone-binding globulin isoform accumulates in the acrosome during spermatogenesis.Selva DM et al
67507271982The serum transport of steroid hormones.Siiteri PK et al
24211561986Steroid-protein interactions II.Westphal U et al
206900692011The (TAAAA)n polymorphism of the SHBG gene in men with the metabolic syndrome.Xita N et al
146711992003Association 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
91951541997Characterisation 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

Gene IDTranscript IDUniprot
ENSG00000129214ENST00000340624I3L145
ENSG00000129214ENST00000380450P04278
ENSG00000129214ENST00000416273P04278
ENSG00000129214ENST00000441599P04278
ENSG00000129214ENST00000570353I3L0M1
ENSG00000129214ENST00000570527I3L4D0
ENSG00000129214ENST00000570547I3L1J1
ENSG00000129214ENST00000571153B0FWH5
ENSG00000129214ENST00000572182I3L1G4
ENSG00000129214ENST00000572262I3L2X4
ENSG00000129214ENST00000574539B4DYU0
ENSG00000129214ENST00000575314I3L145
ENSG00000129214ENST00000575618B0FWH7
ENSG00000129214ENST00000575729I3L1C1
ENSG00000129214ENST00000575903P04278
ENSG00000129214ENST00000576152B0FWH6
ENSG00000129214ENST00000576478I3L4B9
ENSG00000129214ENST00000576728I3L2F1
ENSG00000129214ENST00000576830A0A0C4DGN2

Expression (GTEx)

0
5
10
15
Adipose - Subcutaneous
Adipose - Visceral
Adrenal Gland
Artery - Aorta
Artery - Tibial
Bladder
Brain - Amygdala
Brain - Anterior cingulate cortex
Brain - Caudate
Brain - Cerebellar Hemisphere
Brain - Cerebellum
Brain - Cortex
Brain - Frontal Cortex
Brain - Hippocampus
Brain - Hypothalamus
Brain - Nucleus accumbens
Brain - Putamen
Brain - Spinal cord
Brain - Substantia nigra
Breast - Mammary Tissue
Cells - Cultured fibroblasts
Cells - EBV - transformed lymphocytes
Cervix - Ectocervix
Cervix - Endocervix
Colon - Sigmoid
Colon - Transverse
Esophagus - Gastroesophageal Junction
Esophagus - Mucosa
Esophagus - Muscularis
Fallopian Tube
Heart - Atrial Appendage
Heart - Left Ventricle
Kidney - Cortex
Kidney - Medulla
Liver
Lung
Minor Salivary Gland
Muscle - Skeletal
Nerve - Tibial
Ovary
Pancreas
Pituitary
Prostate
Skin - Not Sun Exposed
Skin - Sun Exposed
Small Intestine - Terminal Ileum
Spleen
Stomach
Testis
Thyroid
Uterus
Vagina
Whole Blood

References

Pubmed IDYearTitleCitations
376059592024The relationship between sex hormone-binding protein and non-alcoholic fatty liver disease using Mendelian randomisation.1
377259122024Sex Hormone-Binding Globulin and Risk of Incident Dementia in Middle-Aged to Older Women: Results from the UK Biobank Cohort Study.1
377350502024Causal relationship between schizophrenia and sex hormone binding globulin: A Mendelian randomization study.0
380513222024The Association Between SHBG and Osteoporosis: A NHANES Cross-Sectional Study and A Bidirectional Mendelian Randomization.0
383202642024Longitudinal Changes in Sex Hormone Binding Globulin (SHBG) and Risk of Incident Diabetes: The Study of Women's Health Across the Nation (SWAN).1
383943592024Association of Testosterone and Sex Hormone-Binding Globulin With All-Cause and Cardiovascular Disease Mortality in Older Chinese Men.0
383968612024Sex-Hormone-Binding Globulin Gene Polymorphisms and Breast Cancer Risk in Caucasian Women of Russia.2
387965762024Blood lipid levels mediating the effects of sex hormone-binding globulin on coronary heart disease: Mendelian randomization and mediation analysis.0
376059592024The relationship between sex hormone-binding protein and non-alcoholic fatty liver disease using Mendelian randomisation.1
377259122024Sex Hormone-Binding Globulin and Risk of Incident Dementia in Middle-Aged to Older Women: Results from the UK Biobank Cohort Study.1
377350502024Causal relationship between schizophrenia and sex hormone binding globulin: A Mendelian randomization study.0
380513222024The Association Between SHBG and Osteoporosis: A NHANES Cross-Sectional Study and A Bidirectional Mendelian Randomization.0
383202642024Longitudinal Changes in Sex Hormone Binding Globulin (SHBG) and Risk of Incident Diabetes: The Study of Women's Health Across the Nation (SWAN).1
383943592024Association of Testosterone and Sex Hormone-Binding Globulin With All-Cause and Cardiovascular Disease Mortality in Older Chinese Men.0
383968612024Sex-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