Sex Determination Flashcards
Pseudoautosomal region of X
The distal region of Xp; many genes that escape inactivation are located here; this is also the site of recombination with Y
3 steps of sexual differentiation
- Establishment of genetic sex through x and Y chromosomes
- Formation of sexually specific gonads
- Development of internal and external reproductive organs
X inactivation
Caused by expanded CpG methylation of the promoters of many (85-90%) genes on one X homolog by DNA methyltransferase
XIST gene
Located within the X inactivation center on Xq and expressed only on the inactive X; produces a non-coding RNA which associates in cis (with the inactive x) to signal DNA methylation and histone modification
Mesonephric (Wolffian) ducts
Thickenings of the genital ridges that give rise to epididymal duct and ductus deferens under the influence of androgens secreted by Leydig cells in the testes
Sertoli cells
In the embryonic testes, produce Mullerian inhibitory substance (MIS) hormone that suppresses formation of the paramesonephric ducts
SRY
Sexual determining region in Y; lies near the pseudo autosomal boundary of the Y chromosome and encodes a TF that is a member of the high mobility group (HMG)-box family of DNA binding proteins
Paramesonephric (Mullerian) ducts
Thickenings of the genital ridges that give rise to the female duct system (fallopian tubes, uterus, and upper vagina) in the absence of male hormonal signals (MIF and testosterone)
DAX1
Located on Xp, encodes a TF that is dosage-sensitive in affecting gonadal sex; duplication of DAX1 suppresses the normal male-determining function of SRY and ovarian development results
DAX1 duplication may leads to XY sex reversal
Intersex Condition
Presence of both ovarian and testicular tissue, generally due to XX/XY chromosomal mosaicism
Camptomelic dysplasia
Autosomal dominant disorder due to mutation in the SOX9 gene on 17q; 75% of XY patients are sex reversed (phenotypic females); skeletal malformations are usually lethal
SOX9
Located on 17q; required for normal testis formation; in its absence, testes fail to form; duplicated copies lead to XX sex reversal (phenotypic males) even in the absence of SRY
Dose-dependent in the development of testes
Mutation of SOX9 in camptomelic dysplasia leads to XY sex reversal in 75% of cases
Dosage Sensitive Sex Reversal (DSS)
Duplication of DAX1 leading to development of ovaries even in the presence of expressed SRY; results in XY sex reversal (phenotypically female)
Nonrandom X inactivation
Preferential inactivation of the inactive X chromosome; however, in the case of an X:autosome translocation, the normal X is preferentially inactivated so as to avoid inactivation of somatic genes
Steroidogenic Factor 1 (SF1)
A nuclear receptor protein located on 9q; expressed in developing gonadal tissues; loss of this gene leads to adrenal hypoplasia and gonadal agenesis
SRY/SOX9/DAX pathway
SRY binds to enhancer elements in the SOX9 gene to upregulate production of SOX protein; SOX protein binds to it’s own enhancer to up-regulate it’s own production, and also represses expression of DAX1
SOX9 contributes to testes development by preventing development of ovaries by suppressing DAX
Sex Reversal
XX males: Y/autosomal translocation
XY females: Deletion of SRY or duplication of DAX
Androgen insensitivity
X-linked mutation of the AR gene which codes for the androgen receptor; individuals are XY but will present with phenotypically female characteristics; infants present with undescended testicles in the inguinal canal
Congenital Adrenal Hyperplasia
Caused by deficiency mutation in the 21-hydroxylase enzyme; normally, this enzyme functions in the synthesis of glucocorticoids; enzymatic deficiency leads to accumulation of precursors which are shunted toward the testosterone synthesis pathway instead, leading to in-utero testosterone exposure; 46 XX individuals present with ambiguous/masculinized genitalia
