W10 L3 Fri Sex chromosome and sex determination 1

Question 1

Different in sex development (DSD)

Answer 1

-DSD are defined as congenital condition in which development of chromosomal, gonodal, phenotypical or brain sex is atypical
- >1% babies are born with some form of DSD
-DSD are rapidly increasing
-most DSD are unexplained by genetic, possible environmental cause

Question 2

clinical presentation of DSD

Answer 2

-DSD recognized at birth (indeterminate sex due to ambiguous genitalia)
-DSD recognized in adolescence: -XX with testes, problem during puberty

Question 3

difficult decision in DSD

Answer 3

-gender assignment versus gender identity
-genital surgery on infant (no consent)
-possible removal of gonad, cancer risk but also reproductive capability
-impact on gender idendity

Question 4

Genetic sex determination

Answer 4

-sex chromosome evolved from autosome
-pseudoautosomal region in the sexchromosome is important for segregation
-SRY gene sometime recombined to X, it is found near the pseudo-autosomal region, can be carried over

Question 5

Discordance of genetic sex rate

Answer 5

-XY female 15% have SRY mutation
-XX male 80% are SRY positive
-XXY kleinfelters (1:1000)
-X0 Turner (1:2500)

Question 6

Phenotype of Turner syndrom

Answer 6

-short stature
-regression of the ovary > gonadal streak
-no mensuration
-masculine feature

Question 7

Phenotype of Klinefelter

Answer 7

-abnormally tall
-femizied characteristic
-female breast development
-impaired IQ
-female pattern pubic hair growth

Question 8

gonad differentiation

Answer 8

-occur in E10.5 in mouse/ week 6-8 in human
-gonad precursor are bipotential (can develop in male or female pattern)
-SRY activate male pathway, if there is no signal > female development pathway
-in male development, vasculature formation and androgenesis cell

Question 9

gonad differentation hormonal pathway

Answer 9

-In male, SRY activate SOX9, FGF9 and DAX1
-In female, activation of WNT4, FST, FOXL2
-male and female gene suppress each other

Question 10

The SRY gene

Answer 10

-single exon gene
-a structural protein have a high mobility box group that bind to DNA and bend its
-expressed in testes
-poorly conserved

Question 11

the poorly conserved SRY

Answer 11

-SRY is only found in some mamal group
-some rodent lost the gene but still have male/female differentiation

Question 12

SRY insertion into female mice experiment result

Answer 12

-XX mouse with SRY transgene
-developed testes
-male behavior and secondary sexual characteristic
-but infertile due to lack of the actual Y chromosome

Question 13

Role of the SRY gene

Answer 13

-SRY transient expression in male
-only turn on for 12 hour in mouse
-to activate SOX9

Question 14

SOX9

Answer 14

-SRY like HMG box containing gene 9
-highly conserved between species
-expressed in cartilage and teste
-autosomal gene

Question 15

Campomelic dysplasia and XY reversal

Answer 15

-sever deficiency in cartilage formation - skeletal defect
-due to mutation in SOX9
- mainly female patients, due to lack of SOX9

Question 16

SOX9 promoter

Answer 16

-SRY lead to activation of SOX9 promoter
-SOX 9 HMG box can bind to it’s own promoter, self upregulation

Question 17

FOXL2

Answer 17

-granulosa cell expresion
-antagonistic to SOX9 in supporting cell
-knock out of FOXL2 lead to partial sex reversal
-mutation of FOXL2 lead to ovarian failure

Question 18

How FOXL2 suppress SOX9

Answer 18

• bind to the promoter region of SOX9 when it is bind to an ER
  -suppress sox9 ovarian development