Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

Keynote webinar | Spotlight on medication adherence

LIVE: Thursday 27th June 2024, 18:00-19:30 (CEST)
Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.
ADVANCED SEARCH
Log in
Top
BMC Medical Genetics
Published in: BMC Medical Genetics 1/2012

Open Access 01-12-2012 | Research article

The CAG repeat polymorphism in the Androgen receptor gene modifies the risk for hypospadias in Caucasians

Authors: Tatjana Adamovic, Agneta Nordenskjöld

Published in: BMC Medical Genetics | Issue 1/2012

Login to get access

Abstract

Background

Hypospadias is a birth defect of the urethra in males, and a milder form of 46,XY disorder of sexual development (DSD). The disease is characterized by a ventrally placed urinary opening due to a premature fetal arrest of the urethra development. Moreover, the Androgen receptor (AR) gene has an essential role in the hormone-dependent stage of sexual development. In addition, longer AR polyglutamine repeat lengths encoded by CAG repeats are associated with lower transcriptional activity in vitro. In the present study, we aimed at investigating the role of the CAG repeat length in the AR gene in hypospadias cases as compared to the controls. Our study included 211 hypospadias and 208 controls of Caucasian origin.

Methods

We amplified the CAG repeat region with PCR, and calculated the difference in the mean CAG repeat length between the hypospadias and control group using the T-test for independent groups.

Results

We detected a significant increase of the CAG repeat length in the hypospadias cases when compared to the controls (contrast estimate: 2.29, 95% Confidence Interval (1.73-2.84); p-value: 0.001). In addition, the odds ratios between the hypospadias and controls revealed that the hypospadias cases are two to 3 times as likely to have longer CAG repeats than a shorter length for each repeat length investigated.

Conclusions

We have investigated the largest number of hypospadias cases with regards to the CAG repeat length, and we provide evidence that a higher number of the CAG repeat sequence in the AR gene have a clear effect on the risk of hypospadias in Caucasians.
Appendix
Available only for authorised users
Literature
1.
Siiteri PK, Wilson JD: Testosterone formation and metabolism during male sexual differentiation in the human embryo. J Clin Endocrinol Metab. 1974, 38: 113-125. 10.1210/jcem-38-1-113.CrossRefPubMed
2.
Kim KS, Liu W, Cunha GR, Russell DW, Huang H, Shapiro E, Baskin LS: Expression of the androgen receptor and 5 alpha-reductase type 2 in the developing human fetal penis and urethra. Cell Tissue Res. 2002, 307: 145-153. 10.1007/s004410100464.CrossRefPubMed
3.
Mooradian AD, Morley JE, Korenman SG: Biological actions of androgens. Endocrine review. 1987, 8: 1-28. 10.1210/edrv-8-1-1.CrossRef
4.
Hiort O, Klauber G, Cendron M, Sinnecker GH, Keim L, Schwinger E, Wolfe HJ, Yandell DW: Molecular characterization of the androgen receptor gene in boys with hypospadias. Eur J Pediatr. 1994, 153: 317-321. 10.1007/BF01956409.CrossRefPubMed
5.
Alléra A, Herbst MA, Griffin JE, Wilson JD, Schweikert HU, McPhaul MJ: Mutations of the androgen receptor coding sequence are infrequent in patients with isolated hypospadias. J Clin Endocrinol Metab. 1995, 80: 2697-2699. 10.1210/jc.80.9.2697.PubMed
6.
Sutherland RW, Wiener JS, Hicks JP, Marcelli M, Gonzales ETJ, Roth DR, Lamb DJ: Androgen receptor gene mutations are rarely associated with isolated penile hypospadias. J Urol. 1996, 156: 828-831. 10.1016/S0022-5347(01)65830-0.CrossRefPubMed
7.
Nordenskjöld A, Friedman E, Tapper-Persson M, Söderhäll C, Leviav A, Svensson J, Anvret M: Screening for mutations in candidate genes for hypospadias. Urol Res. 1999, 27: 49-55. 10.1007/s002400050088.CrossRefPubMed
8.
Wang Y, Li Q, Xu J, Liu Q, Wang W, Lin Y, Ma F, Che T, Li S, Shen Y: Mutation analysis of five candidate genes in Chinese patients with hypospadias. Eur J Hum Genet. 2004, 12: 706-712. 10.1038/sj.ejhg.5201232.CrossRefPubMed
9.
Thai HT, Kalbasi M, Lagerstedt K, Frisén L, Kockum I, Nordenskjöld A: The valine allele of the V89L polymorphism in the 5-alpha-reductase gene confers a reduced risk for hypospadias. J of Endocrinol and Metab. 2005, 90: 6695-6698. 10.1210/jc.2005-0446.CrossRef
10.
Wong HY, Hoogerbrugge JW, Pang KL, van Leeuwen M, van Royen ME, Molier M, Berrevoets CA, Dooijes D, Dubbink HJ, van de Wijngaart DJ, et al: A novel mutation F826L in the human androgen receptor in partial androgen insensitivity syndrome; increased NH2-/COOH-terminal domain interaction and TIF2 co-activation. Mol Cell Biol. 2008, 24: 69-78.
11.
Fredell L, Kockum I, Hansson E, Holmner S, Lundquist L, Läckgren G, Pedersen J, Stenberg A, Westbacke G, Nordenskjöld A: Heredity of hypospadias and the significance of low birth weight. J Urol. 2002, 167: 1423-1427. 10.1016/S0022-5347(05)65334-7.CrossRefPubMed
12.
Lim HN, Chen H, McBride S, Dunning AM, Nixon RM, Hughes IA, Hawkins JR: Longer polyglutamine tracts in the androgen receptor are associated with moderate to severe undermasculinized genitalia in XY males. Hum Mol Genet. 2000, 22: 829-834.CrossRef
13.
Aschim EL, Nordenskjöld A, Giwercman A, Lundin KB, Ruhayel Y, Haugen TB, Grotmol T, Giwercman YL: Linkage between cryptorchidism, hypospadias, and GGN repeat length in the androgen receptor gene. J Clin Endocrinol Metab. 2004, 89: 5105-5109. 10.1210/jc.2004-0293.CrossRefPubMed
14.
Muroya K, Sasagawa I, Suzuki Y, Nakada T, Ishii T, Ogata T: Hypospadias and the androgen receptor gene: mutation screening and CAG repeat length analysis. Mol Hum Reprod. 2001, 7: 409-413. 10.1093/molehr/7.5.409.CrossRefPubMed
15.
Chamberlain NL, Driver ED, Miesfeld RL: The length and location of CAG trinucleotide repeats in the androgen receptor N-terminal domain affect transactivation function. Nucleic Acids Res. 1994, 22: 3181-3186. 10.1093/nar/22.15.3181.CrossRefPubMedPubMedCentral
16.
La Spada AR, Wilson EM, Lubahn DB, Harding AE, Fischbeck KH: Androgen receptor gene mutation in X-linked spinal and bulbar muscular atrophy. Nature. 1991, 352: 77-79. 10.1038/352077a0.CrossRefPubMed
17.
La Spada AR, Roling D, Harding AE, Warner CL, Spiegel R, Hausmanowa-Petrusewicz I, Yee WC, Fischbeck KH: Meiotic stability and genotype-phenoype correlation of the trinucleotide repeat in X-linked spinal and bulbar muscular atrophy. Nat Genet. 1992, 2: 301-304. 10.1038/ng1292-301.CrossRefPubMed
18.
Edwards CA, Hammond HA, Jin L, Caskey CT, Chakraborty R: Genetic variation in five trimeric and tetrameric tandem repeat loci in four human population groups. Genomics. 1992, 12: 241-253. 10.1016/0888-7543(92)90371-X.CrossRefPubMed
19.
Radpour R, Rezaee M, Tavasoly A, Solati S, Saleki A: Association of long polyglycine tracts (GGN repeats) in exon 1 of the androgen receptor gene with cryptorchidism and penile hypospadias in Iranian patients. J Androl. 2007, 28: 164-169.CrossRefPubMed
20.
Sambrook J, Fritsch E, Maniatis T: Isolation of high molecular weight DNA from mammalian cells. 1989, Molecular Cloning New York: Cold Spring Harbour Laboratory Press, 14-23.
Metadata
Title
The CAG repeat polymorphism in the Androgen receptor gene modifies the risk for hypospadias in Caucasians
Authors
Tatjana Adamovic
Agneta Nordenskjöld
Publication date
01-12-2012
Publisher
BioMed Central
Published in
BMC Medical Genetics / Issue 1/2012
Electronic ISSN: 1471-2350
DOI
https://doi.org/10.1186/1471-2350-13-109

Other articles of this Issue 1/2012

BMC Medical Genetics 1/2012 Go to the issue

Research article

Investigating the relationship between UMODL1 gene polymorphisms and high myopia: a case–control study in Chinese

Research article

High-resolution SNP array analysis of patients with developmental disorder and normal array CGH results

Research article

Genotype-phenotype correlation in 22q11.2 deletion syndrome

Research article

A case-only study of gene-environment interaction between genetic susceptibility variants in NOD2 and cigarette smoking in Crohn's disease aetiology

Research article

The MAP2K5-linked SNP rs2241423 is associated with BMI and obesity in two cohorts of Swedish and Greek children

Research article

Non-replication study of a genome-wide association study for hypertension and blood pressure in African Americans