Reproductive Genetics: Sex Determination Mechanisms and Genetic Abnormalities

1. Sex:

Sex is a biological characteristic that distinguishes individuals as male or female. It is determined by:

• Genetic sex (genotype): Determined by the combination of sex chromosomes (sex chromosomes). In humans, females have a pair of XX sex chromosomes, while males have a pair of XY sex chromosomes.

• Primordial sex (gonadal sex): Determined by the development of gonads (testes or ovaries).

• Phenotypic sex: The external manifestation of sex, including primary sex characteristics (genitals) and secondary sex characteristics (voice, body shape, hair…).

2. Testis-determining gene (TDF):

• Located on the Yp11.2 region of the Y chromosome.

• Contains the SRY (Sex-determining Region Y) gene, which is the main gene that activates the pathway for testis determination.

3. Genes involved in sex determination:

• SRY (Sex-determining Region Y):

• Located on the Yp11.2 region of the Y chromosome.

• Initiates the testis-determining pathway, playing a crucial role in the development of testes.

• Upregulates the SOX9 gene through transcriptional regulation.

• SOX9 (Sex-determining Region Y-box 9):

• Located on the 17p24.3 region of chromosome 17.

• Plays a key role in the differentiation of testes from the indifferent gonad.

• Determines the differentiation of pre-Sertoli cells into Sertoli cells, which produce anti-Müllerian hormone (AMH).

• DAX1 (Dosage-sensitive sex reversal adrenal hypoplasia congenital critical region on the X chromosome gene 1):

• Located on the Xp21.2 region of the X chromosome.

• Expressed in ovarian development.

• SF-1 (Steroidogenic factor 1):

• Located on the 9p33.3 region of chromosome 9.

• Involved in the formation of the indifferent gonad.

• WT1 (Wilms tumor 1):

• Located on the 11p13 region of chromosome 11.

• Involved in the formation of the indifferent gonad.

4. Genes involved in sex differentiation:

• Hormone-dependent sex differentiation:

• AMH (Anti-Müllerian hormone): Initiates the regression of the Müllerian ducts, leading to the development of the Wolffian ducts into vas deferens, prostate, and seminal vesicles.

• AMH gene: Located on the 19p13.3 region of chromosome 19.

• No AMH: The Müllerian ducts will develop into the uterus, fallopian tubes, and vagina; the Wolffian ducts will regress.

5. Infertility:

• Non-obstructive infertility (60%): Males are unable to produce sperm due to:

• Undescended testes.

• Down syndrome, Klinefelter syndrome, 46-XX.

• Cystic fibrosis.

• Obstructive infertility (40%): Sperm production is normal, but the vas deferens is blocked.

6. Klinefelter syndrome (47, XXY):

• The most common sex chromosome abnormality in males (1/500-1000).

• Clinical symptoms:

• Tall stature with long limbs.

• Small testes with no sperm (checked by semen analysis).

• Usually not intellectually impaired, but slower than peers.

• Slightly feminine body features.

• Usually diagnosed during infertility investigations.

7. 47XYY:

• Frequency: 1/1000.

• Clinical symptoms:

• Tall stature, learning difficulties, delayed speech and motor development, muscle weakness, hand tremors, hyperactivity, decreased attention, autistic spectrum.

• May be fertile: Some cases have low sperm count or no sperm.

8. Male 46XX:

• Frequency: 1/2500.

• Abnormalities in XY crossover during meiosis.

• Clinical symptoms:

• 20% have ambiguous external genitalia at birth.

• 80% experience decreased spermatogenic function after puberty, small testes, infertility.

• Absence of sperm may be due to the absence of AZF.

9. AZF (Azoospermia factor):

• Genes encoding for spermatogenesis.

• Y chromosome deletions affecting AZF can lead to infertility.

10. Y chromosome deletions:

• 10% of men with low sperm count, 15% of infertile patients.

• Disrupt spermatogenesis.

11. Gene mutations in obstructive infertility:

• Congenital bilateral absence of the vas deferens: CFTR mutations.

• Congenital unilateral absence of the vas deferens: Mutations in other genes.

12. Gene mutations in non-obstructive infertility:

• TEX11, DMC1, DNAH6, MAGEB4.

13. Primary amenorrhea:

• Includes:

• Outflow tract abnormalities (20%): Vaginal septum, vaginal atresia…

• Primary ovarian insufficiency (40%): Ovaries are not functioning or are poorly functioning.

• Central abnormalities (35%): Pituitary disorders, hypopituitarism…

• Other endocrine disorders: Hypothyroidism, hyperthyroidism…

14. Abnormalities in primary ovarian insufficiency:

• Gonadal dysgenesis: Turner syndrome, Swyer syndrome…

• Gene mutations: Premutations in fragile X syndrome, galactosemia, BPES syndrome…

• Enzyme deficiencies: Deficiency of 17 alpha hydroxylase, 20,22 desmolase…

• Autoimmune diseases: Autoimmune oophoritis…

• Damage from chemotherapy/radiotherapy: Due to cancer treatment.

15. Gonadal dysgenesis:

• Turner syndrome (45,X):

• Frequency: 1/2500-4000.

• 99% of monosomy X miscarriages.

• Classification:

• Monosomy X (45,X): Most common.

• Mosaicism: 45X-46XX (most common), 45X-46XY (rare).

• Structural chromosomal abnormalities: Isodicentric X, X chromosome deletion, ring X.

• Clinical symptoms:

• Proportional dwarfism.

• Sex differentiation: 40-50% have signs of puberty, 10% have menstruation.

• Most are infertile.

• Malformations: bones, kidneys (horseshoe kidney), heart.

• Usually no intellectual disability.

• Swyer syndrome (46,XY complete gonadal dysgenesis):

• Frequency: 1/80,000.

• Female external genitalia.

• Uterus and fallopian tubes are normal.

• Gonads are streak-like.

• Causes of Swyer syndrome:

• SRY mutations.

• MAP3K1 mutations (decreased female sex differentiation).

• DHH, NIR5A1 mutations.

16. Fragile X syndrome:

• More common in males.

• Females carrying a premutation experience premature ovarian insufficiency.

• Related to CGG repeats on the X chromosome.

• CGG repeats:

• Less than 55 times: normal.

• 55 to 200 times: premutation.

• Over 200 times: full mutation.

Note:

• This article is for general information purposes only and does not substitute for professional medical advice.

• Information on frequency and clinical symptoms is for reference only.

• If you have any health concerns, please contact a doctor for advice and timely treatment.

Additional Information:

• The article should include information about diagnostic methods and treatments for genetic abnormalities related to sex.

• Additionally, the article can be expanded to address social issues related to sex, such as transgender rights.