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)