Abnomalities in sex determination I and II Flashcards
What is sex determination
process by which genetic sex determines gonadal sex, the testis or ovary. Sex differentiation follows and is the process by which the now determined gonads and their respective hormones direct the differentiation of the internal and external genitalia
XX and XY sex determinants
XX: Rspo1 and Wnt4
XY: SRY and Sox9
Gonadal sex determination
choice between two mutually opposing fats
genital ridges contain at least 3 types of unspecified, bipotential precursor cell
In XY gonads, cells of the supporting cell lineage start to express Sry and then Sox9, causing them to differentiate into Sertoli cells. In the absence of Sry, as in XX genital ridges, the same precursor cells differentiate into granulosa cells under the influence of genes encoding transcription factors, including Ctnnb1 and Foxl2. In addition to promoting the Sertoli cell differentiation pathway, Sry and Sox9 also (directly or indirectly) suppress female-specific cell differentiation pathways. Sertoli cells induce (dotted arrows) other cell populations to differentiate into the steroidogenic FLCs that otherwise would differentiate into ovarian theca cells and enter the spermatogenic pathway as opposed to the oocyte differentiation pathway.
significance of sertoli cells
are the organizing center of testis differentiation
they are the first somatic cells to differentiate in the xy gonad
they influence testis cord formation, mullerian duct regression and differentiation and function of several other cell types
cellular mechanism of SRY function
in cytoplasm SRY bound by calmodulin (CaM) and importin beta (Impb)
recognize the N- and C- terminal nuclear localization signals on SRY= recruit it to enter the nucleus
SRY and steroidogenic factor bind directly to specific sites (tesco- testis specific enahncer of Sox9 core) that lie within gonadal specific enhances of Sox9
upregulates Sox9 expression
XY sex reversal
phenotype: ovaries, female genetalia and secondary characteristics
genes or other alterations: SRY, SOX9
campometic dysplasia
phenotye: skeletal dysmorphology and Xy sex reversal
alteration: sox9
Sox9 transcriptional reg in gonad
three phases: initiation, upregulation, maintenance
SF1 sensitizes Sox9, initiating a low level of expression in the genital ridge of both sexes
in male also activates Sry expression
Sox9 expression is upregulated by the action of SRY together with SF1, whereas it is downregulated in the female. This downregulation is unlikely to be passive, implying the presence of one or more currently unknown repressors. After the transient expression of Sry has ceased, high levels of SOX9 are maintained by its direct autoregulation and via FGF9 signaling
. SOX9 binds directly to the enhancer, replacing SRY at some sites, but because the SOX9 HMG box can physically interact with the SF1 C-terminal domain, the two proteins also recruit each other to additional binding sites.
Campomeliac dysplasia characteristics
small thoracic cage small scapulae 11 pairs of ribs small iliac wings mild bowing of femor and tibia bilaterally
genetics of human sex determination in females
WNT4 and RSPO1 act through Frizzled or LRP5–LRP6 receptors to activate β-catenin (CTNNB1) transcription. β-catenin and FOXL2 promote expression of ovary-specific genes while inhibiting the expression of testis factors such as SOX9.
genetics of human sex determination in males
Map-kinase signalling through MAP3K1 may alter chromatin conformation indirectly through histone modifications (dotted arrow). Map-kinase signalling also increases phosphorylation of transcription factors such as GATA4, which is thought to alter chromatin (dotted arrow) upstream of SRY, and was shown to directly bind to SRY promoter (solid arrow) to activate transcription. Within the nucleus, transcription factors GATA4 and ZFPM2 bind and transactivate SRY and SOX9. Other important factors are CBX2 that has been shown to directly bind the SRY promoter and that, in conjunction with the NR5A1 protein, binds to the SOX9 promoter. The SRY protein can then turn on downstream genes such as SOX9, which initiates the testis gene expression network and represses ovarian-specific genes such as RSPO1 and β-catenin.
Wt1
wilms tumor 1
transcription factor
disorders related to WT1 mutation (3)
Denys-Drash syndrome
Frasier syndrome
WAGR syndrome
Denys-Drash syndrome
WTI mutation
pseudohermaphroditism, nephropahty, predisposition to Wilms tumor
gonadal dysgenesis
missense mutations in the zinc-finger domain and premature trancuations
mutation WT1 and -KTS
very rare disorder
changes in certain exons (9 and 8) and mutations in some alleles of WT1 (11p13)
condition first manifests as early nephrotic syndrome and progresses to mesangial renal sclerosis and ultimately renal failure, usually within the first three years of life
Frasier Syndrome
presents at birth with male Pseudohermaphroditism, external genitalia have a female appearance despite XY genotype
streak gonads and progressive glomerulopathy
urogenital anomly
WTI mutation
splice donor site mutation in intron 9
increased risk of genitourinary tumors (usually gonadoblastoma)
Diminished +KTS
WAGR syndrome
WT1 mutation- constitutional deletion
wilms tumor, anirdia, genito-urinary malformations, mental retardation
Wilms tumor
mostly nonsense mutation Loss of heterozygosit
loss maternal allele of polymorphic marker A
proteins that interact with WT1
p53
PAR-4 localized in the zing finger region
ubiquitin-conjugating enzyme 9 (UBC9) and HSP70
steroidogenic factor (SF-1)
more on Frasier syndrome
clinical presentation usually occurs between 2 and 3rd decades- most cases at puberty
male pseudohermaphorditism: phenotypically female patients presenting with amenorrhea
XY karyotype: streak (dysgenetic) gonads with gonadoblastoma, normal external female genitalia, clitoris enlargment, and ambigous genitalia may be present, small uterus
nephrotic syndrome with slowly progressing renal disease, resulting in end-stage renal failure
focal and segmental glomeruloscleroisis: in later stages of renal disease, only chrnoic, nonspecific findings may be present in kidney biopsy
XX karytype: patients with less severe phenotype, frequently not clinically identified as FS
- normal and functioning female genitalia
- clinically present only with renal disease
WTI1 in maintainance of adult tissue homeostasis
deletion of WT1 in adult mice leads to severe glomerosclerosis, massive atrophy of exocrine pancrease, defects in erythropoiesis, and rapid loss of bone and adipose tissue
highlights of WT1 and TET2
WT1 is mutated in a mutally exclussive manner with TET2, IDH1 and 2 in AML
WT1 recruits TET2 to its target genes
AML-derived mutations in TET2 disrupt its binding with WT1\
WT1 and TET2 are functionally interdependent
Sketon and SOX9
campomelic dysplasia
Kidney and WT1
wilms tumor
denys-drash syndrome
frasier syndrome
gonads and RSPO1
ovary
gonads and SRY
testis
phenotypes resulting from genetic ablations or mutations of the orphan nuclear receptor SF-1
Adrenal- agenesis- hisological defects, hyporesponse to stress, compensatory growht factors- insufficiency
Testis- agenesis, sex reversal
Ovary- agenesis
VMH-agenesis, obesity caused by absence of VmH
pituitary- defects of gonadotrope cells
Congential Adrenal Hypoplasia
DAX1 mutation
adrenal hypoplasia, hypogonadotropic hypogonadism
9p- syndrome
rare disorder with deletion of DMRT coding region 9p24.3
gene is found in a cluster with two other members of the gene family, having in common a zinc-finger-like DNA binding motif
DM domain ancient, conserved component of the vertebrate sex-determining pathway
gene exhibitis a gonad specific and sexually dimoprhic expression pattern, just like the related doublesex gene in fruit flies
defective testicular development and XY feminization = 46 XY gonadal dysgenesis occurs when this gene is hemizygous
Sertoli cells is the organizing center for:
germ cell differentiation PMC differentiation EC arterialization cord formation mullerian duct regression FLC differentiation
