Sex Determination

Question 0

Pseudoautosomal region of X

Answer 0

The distal region of Xp; many genes that escape inactivation are located here; this is also the site of recombination with Y

Question 1

3 steps of sexual differentiation

Answer 1

1. Establishment of genetic sex through x and Y chromosomes
2. Formation of sexually specific gonads
3. Development of internal and external reproductive organs

Question 2

X inactivation

Answer 2

Caused by expanded CpG methylation of the promoters of many (85-90%) genes on one X homolog by DNA methyltransferase

Question 3

XIST gene

Answer 3

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

Question 5

Mesonephric (Wolffian) ducts

Answer 5

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

Question 6

Sertoli cells

Answer 6

In the embryonic testes, produce Mullerian inhibitory substance (MIS) hormone that suppresses formation of the paramesonephric ducts

Question 6

SRY

Answer 6

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

Question 7

Paramesonephric (Mullerian) ducts

Answer 7

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)

Question 9

DAX1

Answer 9

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

Question 9

Intersex Condition

Answer 9

Presence of both ovarian and testicular tissue, generally due to XX/XY chromosomal mosaicism

Question 10

Camptomelic dysplasia

Answer 10

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

Question 11

SOX9

Answer 11

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

Question 12

Dosage Sensitive Sex Reversal (DSS)

Answer 12

Duplication of DAX1 leading to development of ovaries even in the presence of expressed SRY; results in XY sex reversal (phenotypically female)

Question 13

Nonrandom X inactivation

Answer 13

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

Question 14

Steroidogenic Factor 1 (SF1)

Answer 14

A nuclear receptor protein located on 9q; expressed in developing gonadal tissues; loss of this gene leads to adrenal hypoplasia and gonadal agenesis

Question 15

SRY/SOX9/DAX pathway

Answer 15

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

Question 16

Sex Reversal

Answer 16

XX males: Y/autosomal translocation

XY females: Deletion of SRY or duplication of DAX

Question 18

Androgen insensitivity

Answer 18

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

Question 19

Congenital Adrenal Hyperplasia

Answer 19

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