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10th Postgraduate Course for Training in Reproductive Medicine and Reproductive Biology

Genes implicated in sexual differentiation

Marguerite Neerman-Arbez, Ph.D.
Division of Medical Genetics, C.M.U.

Recommended review article for this topic: MacLean et al., 1997. Clin Endocrinol. 46:101-108.

Four levels of sexual development:
  1. Chromosomal sex (XX/XY)
  2. Gonadal sex (ovary/testicle)
  3. Phenotypic sex (female or male)
  4. Behaviour/ psychological sex
Chromosomal sex:
  • XX : female
  • XY : male
Sex determination:
  • Number of Xs?
  • Number of Ys?
  • Ratio X/Y?
  • N.B.
  • in Drosophila: ratio X/A;
  • in birds: ZW females, ZZ males
  • turtles (T° dependent)
  • fish: sex reversal according to population densities
  • woodlouse: "sex by infection"
Chromosomal aneuploidies in man:
  1. XO Turner syndrome
  2. XXY Klinefelter syndrome
  3. Other combinations:
  4. XXX, XXXX females
  5. XXXY, XXXXY males
Sex reversed individuals:
  1. XX males ( approx. 1/20 000 males)
  2. XY females (not ambiguous genitalia )

>>>> TDF concept

Evidence that SRY is TDF:
  1. Homologues of SRY have been identified on all mammalian Y chromosomes studied so far
  2. SRY is in the smallest interval on Y necessary for male development
  3. SRY is expressed immediately before testis formation
  4. mutations in SRY cause sex-reversal
  5. XX mice transgenic for SRY develop as males
Structure and function of SRY:
  • One exon gene
  • 120 amino acids
  • conserved 80 a.a. motif with homology to HMG (High Mobility Group) proteins "HMG box"
  • DNA-binding protein (recognises A/TACAAT)
  • DNA-bending protein
  • Role in transcriptional control?
Mutations in SRY:
  • XY females
  • All SRY mutations identified so far are in the conserved HMG box. Most are de novo, the majority occurring in the father's germline or early in embryonic development.
  • Some familial cases. However, only 15% of XY females have mutations in SRY
  • other genes are involved
  • XY females with a normal SRY and complete gonadal dysgenesis suggest mutations in genes upstream from SRY
  • XY females with a normal SRY and incomplete gonadal dysgenesis suggest mutations in genes downstream from SRY
WT1 and Denys-Drash Syndrome:
  • XY individuals with
  • feminisation of external genitalia
  • persistent Mullerian structures
  • nephropathy
  • Wilms tumour
  • Mutations in WT1 gene (11p)
  • Tumour suppressor gene
  • Expression in the foetal primordial kidney/gonad
  • Zinc finger DNA binding transcription factor
  • Upstream of SRY?
SOX 9 and campomelic dysplasia:
  • 2/3 XY individuals develop as phenotypic females or intersex
  • associated with severe skeletal abnormalities
  • Mutations in SOX 9 (17q)
  • Member of the SRY DNA binding protein family
  • Expression of SOX 9 and SRY in same tissues (interaction?)
  • Dosage of SOX 9 critical for function (heterozygote loss of function causes the disease)
DSS (Dosage sensitive sex reversal):
  • XY individuals with female external genitalia and dysgenetic gonads.
  • Duplication of a region of Xp21
  • DSS locus but gene is still unidentified
  • SRY + 2 copies DSS >>> no testicles formed
  • DSS may be necessary for ovarian development (positive signal for female differentiation) which can be repressed by SRY if 1 copy of DSS present
DAX1 gene
  • mapped to locus, member of nuclear hormone receptor superfamily
  • Gene for ACH (adrenal congenita hypoplasia)
  • Expression in the developing indifferentiated gonad and continues in the developing ovary
  • Interaction DAX1/SF-1?
MIS/MIS receptor and PMDS (persistent Müllerian duct syndrome):
  • XY phenotypic males with
  • presence of uterus and Fallopian tubes
  • often associated with cryptorchidism
  • Mutations either in the MIS/AMH gene (19p) or MIS/AMH receptor gene (12q)
  • MIS expression is regulated by interaction of SF-1 with promoter of MIS
  • MIS gene contains putative SRY binding site (but role of SRY in MIS expression may be indirect)