A new point mutation of the androgen receptor gene in a patient with partial androgen resistance and severe oligozoosper

1. A new point mutation of the androgen receptor gene in a patient with partial androgen resistance and severe oligozoospermia Research Presented By: Jameliya L. Hall Seminar 475-01 October 13, 2003 Knoke, I., S. Jakubiczka, H. Lehnert, and P. Wieacker. 1999. A new point mutation of the androgen receptor gene in a patient with partial androgen resistance and severe oligozoospermia. Andrologia 31:199-201

2. Introduction What is Androgen Insensitivity Syndrome (AIS) • Genetic Disorder • X-linked • Recessive • Child XX • Carrier • Develop into normal female • Child XY • Develop with AIS © Warne G.L. “Androgen Insensitivity Syndrome” 1997

3. Introduction How is AIS Caused? • Cause: Mutation in Androgen receptor (AR) • AR located on long arm of X chromosome • Chemical in androgen-responsive cells • Receives the messages carried by the androgens/ starts the response in the cell • AR (member of group of steroid hormone receptor genes) • 8 exons coding for approx. 919 amino acids © http://ww2.mcgill.ca/androgendb/ARmodel.jpg

4. Exon • Nucleotide sequence in a primary RNA transcript • Preserved in the mature, functional RNA molecule

5. Codon • A sequence of three adjacent nucleotides • Location: messenger RNA (mRNA) molecule • Determines the insertion of a specific amino acid during protein synthesis.

6. Androgen and Sexual Development • In womb it is impossible to distinguish male genitalia from female genitalia • Both sexes include: midline cleft with ball at the top (the location of future penis or clitoris) • Neutral stage develops into either male or female genitalia

7. Sexual Development with Androgen • Testes start producing androgen • Button grows into a penis • The cleft crosses over • Urinary opening moves towards tip of penis • The scrotum forms © Warne G.L. “Androgen Insensitivity Syndrome” 1997

8. Sexual Development without Androgen • Neutral stage develops into normal female genitalia • Androgen not produced in female fetus • Clitoris remains small and cleft stays open © Warne G.L. “Androgen Insensitivity Syndrome” 1997

9. Sexual Development with AIS • Testes produce androgen (masculine changes only occur in response to androgen) • However, the genitals are unable to respond to androgen • External genitals develop into a female, because natural development in the fetus is to become a female

10. Types of AIS • Complete: (CAIS) body completely unresponsive to androgens (female external genitalia) • Partial: (PAIS) body partially responsive to androgens (genital ambiguity) • Minimal: (MAIS) body has minimal response to androgens (normal male genitalia, infertility)

11. Missense Mutation • Missense: Mutation that changes a codon for one amino acid into a codon for a different amino acid. • Mutation: The change in a base sequence of a DNA molecule • Very Common, 85% occur in the steroid-binding domain

12. What is the Rational? • Identification of a mutation that changes a codon for one amino acid into a codon for a different amino acid in the AR of a male with mild features of AIS.

13. Independent Variable vs. Dependent Variable • Independent Variables: Patient with partial androgen resistance and the Control • Dependent Variable: AIS (Type of mutations observed in the AR gene)

14. Patient: 30 year old male Approx. 155.426 pounds Approx. 5.67585 feet Abnormalities in patients’ genitals since birth Age 12: corrective surgery for genital abnormalities Age 12-13: breast developed Testes volume measured as 11 and 10 ml Background Patient

15. Sperm Count (very low) <01. million ml-1 Normal >20 million Luteinizing Hormone [LH] (elevated) <9.8 U 1 -1 Normal <6 U 1 -1 Testosterone (normal) 14.2 ng ml -1 Follicle Stimulating Hormone [FSH] (normal) 5.9 U 1-1 Background Patient

16. Supporting Data • A point mutation (GTCCTC) in codon 911 in exon H • Since each nucleotide codes for an amino acid this tranversion leads to a valine (C5H11NO2) to leucine (C6H13NO2) substitution

17. Supporting Data • A = Patient • B = Control Person

18. Conclusion • Point mutation (Val911Leu) in exon H • GTC codes for Valine and CTC codes for leucine • A mutation found in the steroid binding domain of the AR gene changes a codon for one amino acid into a codon for a different amino acid

19. Bibliography • Knoke, I., S. Jakubiczka, H. Lehnert, and P. Wieacker. 1999. A new point mutation of the androgen receptor gene in a patient with partial androgen resistance and severe oligozoospermia. Andrologia 31:199-201 • Pease, R.W. editor. 1996. Merriam webster’s medical desk dictionary. Merriam-Webster Inc., Springfield. • Warne, G.L. 1997. Complete androgen insensitivity syndrome. Pp. 14. Department of Endocrinology and diabetes, Australia. • http://www.sciencemadesimple.net/conversions.html • http://www.dictionary.com • http://www.wikipedia.org

20. Bibliography • http://ww2.mcgill.ca/androgendb/ARmodel.jpg • http://www.bsped.org.uk/NN/CAIS.htm • http://hdklab.wustl.edu/lab_manual/dna/dna2.html • http://www.gpnotebook.co.uk/cache/-1221263285.htm • http://www.ich.ucl.ac.uk/cmgs/argene98.htm

21. THE END…. ANY QUESTIONS ???