Brainscape's Knowledge GenomeTM


Top Flashcards (Certified)
All Flashcards

Y Sexual Genetics > Abnomalities in sex determination I and II > Flashcards

Abnomalities in sex determination I and II Flashcards

1
Q

What is sex determination

A

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

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
2
Q

XX and XY sex determinants

A

XX: Rspo1 and Wnt4

XY: SRY and Sox9

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
3
Q

Gonadal sex determination

A

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.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
4
Q

significance of sertoli cells

A

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

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
5
Q

cellular mechanism of SRY function

A

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

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
6
Q

XY sex reversal

A

phenotype: ovaries, female genetalia and secondary characteristics

genes or other alterations: SRY, SOX9

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
7
Q

campometic dysplasia

A

phenotye: skeletal dysmorphology and Xy sex reversal
alteration: sox9

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
8
Q

Sox9 transcriptional reg in gonad

A

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.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
9
Q

Campomeliac dysplasia characteristics

A 
small thoracic cage
small scapulae
11 pairs of ribs
small iliac wings
mild bowing of femor and tibia bilaterally
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
10
Q

genetics of human sex determination in females

A

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.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
11
Q

genetics of human sex determination in males

A

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.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
12
Q

Wt1

A

wilms tumor 1

transcription factor

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
13
Q

disorders related to WT1 mutation (3)

A

Denys-Drash syndrome
Frasier syndrome
WAGR syndrome

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
14
Q

Denys-Drash syndrome

A

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

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
15
Q

Frasier Syndrome

A

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

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
16
Q

WAGR syndrome

A

WT1 mutation- constitutional deletion

wilms tumor, anirdia, genito-urinary malformations, mental retardation

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
17
Q

Wilms tumor

A

mostly nonsense mutation Loss of heterozygosit

loss maternal allele of polymorphic marker A

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
18
Q

proteins that interact with WT1

A

p53
PAR-4 localized in the zing finger region
ubiquitin-conjugating enzyme 9 (UBC9) and HSP70
steroidogenic factor (SF-1)

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
19
Q

more on Frasier syndrome

A

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
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
20
Q

WTI1 in maintainance of adult tissue homeostasis

A

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

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
21
Q

highlights of WT1 and TET2

A

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

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
22
Q

Sketon and SOX9

A

campomelic dysplasia

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
23
Q

Kidney and WT1

A

wilms tumor
denys-drash syndrome
frasier syndrome

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
24
Q

gonads and RSPO1

A

ovary

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
25
gonads and SRY
testis
26
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
27
Congential Adrenal Hypoplasia
DAX1 mutation adrenal hypoplasia, hypogonadotropic hypogonadism
28
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
29
Sertoli cells is the organizing center for:
``` germ cell differentiation PMC differentiation EC arterialization cord formation mullerian duct regression FLC differentiation ```
30
FLC differentiation is important in
brain differentiation testis descent penis/scrotum differentiation wolffian duct differentiation
31
How is SRY involved in the development of testis/ovary
Model of Sox9 Regulation Required for Maintenance of Gonadal Phenotype in MammalsDuring initial phases of sex determination, SRY upregulates Sox9 expression, and subsequent positive autoregulatory loops involving SOX9 itself, together with FGF9 and prostaglandin D2 signaling, activate and maintain Sox9 expression in male gonads, whereas β-catenin stabilized by WNT4 and RSPO1 signaling suppresses Sox9 expression in female gonads. After birth β-catenin activity declines and thus in adult female gonads, FOXL2 and estrogen receptors (ESR1/2) are required to actively repress Sox9 expression to ensure ovarian somatic cell fate. The transcriptional repression of Sox9 by FOXL2 and estrogen receptors is necessary throughout the lifetime of the female to prevent transdifferentiation of the somatic compartment of the ovary into a testis (PTGDS, prostaglandin D synthase).
32
DMRT1
upregulates male-specfic mRNA's upregulates Ptgdfr, Fgf9, Sox9 and Sox 8 inhibits Foxl2/Esr1,2, Wnt4, and Rspo1- so inhibits female differentiation
33
major steps in male differentiation
1. development of external genitalia 2. formation of the aorta-genital-ridge mesonephros region 3. testis and genital tract differentiation 4. testicular descent 5. development of brain dimorphisms
34
development of the mammalian gonads
urogenital ridge --> bipotential gonad EMX2, LHX9, M33, WT1-KTS, SF-1 WT1+KTS, GATA4/FOG2, SRY, SF-1, DAX1, FGF9 --> Testis DHH, PDGFRa, WNT4, ARX, SF-1--> AMH, INSL3, Testosterone or PISRT1/FOXL2 --> Ovary
35
What happens during male testis developmetn
coelomic arterial vessel and male vascularisation germ cell migration/prolifferation inhibition of PGC meoiss by mitotic arrest sertoli prolifferation/differentiation Leyding cell migration/differentiation PTM cell migration/proliferation Testis cord formation
36
Function of: Leydig Sertoli Germ cells
Leydig- testosterone, Insl3 Sertoli- MIS, inhibin B Germ cells- spermatogenesis
37
what happens during ovary developmetn
inhibit coelomic vascularization germ cells migration/proliferation cell autonomous PGC meiotic entry
38
function: Theca Granulosa Germ cells
Theca- estrogen Granulosa- Folliculogenesis Germ cells- oogenesis
39
FLC (fetal leyding cells) affect on male sexual development`
steroidogenic cells, and both the FLCs and ALCs are responsible for producing androgens. During fetal life, androgens induce the Wolffian ducts to form epididymides, vasa deferentia, and seminal vesicles. Androgens further stimulate the elongation of the genital tubercle to form the penis and tissue fusion to form the penile shaft and scrotum. FLCs also produce factors necessary for testicular descent, including INSL3. Evidence strongly suggests that sex hormones influence differences in brain development between the sexes, but the factors involved remain unknown
40
Cryptorchid
failure or problems with testicular descent highly heritable unilateral or bilateral germ cells fail to multiply and then die, Sertoli cells only in seminiferous tubules high percentage develop testicular cancer surgical correction possible but does not reduce cancer risk
41
factors affecting transabdominal testicular descent
INSL3, LGR8, Estrogens
42
factors affecting inguinoscrotal testicular descent
Androgens, androgen receptor genes, gonadotropins, GFN, CGRP
43
other factors affecting testicular descent
HoxA10, AMH, AMH receptor gene
44
alpha thalassaemia
``` mental retardation x-linked genital abnormalities facial anomalies lung, kidney and digestive problems mild from of hemoglobin H disease facial features include: microcephaly, hypertelorism, epicanthus, small triangle upturned nose, flat face ``` mutation: ATRX alpha thalassemia mental retardation X-linked
45
Androgen insensitivity syndrome
AR | vary from nearly normal male to nearly normal female
46
Hypospadias subgroups and whats in them
Anterior: hypospadias sine, hypospadias, glandular, (sub)coronal middle: distal penile, midshaft, proximal penile posterior: penoscrotal, scrotal, perneal
47
ATRX is expressed in
Sertoli cells throughout testicular development
48
what does ATRX recognize
chromatin remodeler so recognizes histone-modification states and modulates chromatin dynamics in vivo
49
what is ATRX involved in
organization of pericentric heterochromatin normal cells: establishment and maintenance of high order PCH packing defects in PCH strucuture- chromosome missegregation- apoptosis of neuroprogenitors?
50
ATRX is also involved in:
telomere organization ATRX or DAXX mutation: telomere dysfunction genomic instability altered gene expression
51
how might ATRX regulate genes involved in testicular development via chromatin remodeling
a) association with enahncer of zeste and through its protein, embryonic ectoderm development 4-8, functions as a transcriptional factor repression complex with histone deacetylases b) complex with chromatin-associated repression protein which interacts directly with the DNA methyltransferase through ATRX-like domain of Dnmt3a
52
Model for how ATRX might influence gene expression
ATRX is part of a multiprotein complex that uses the energy of ATP to remodel chromatin or its associated DNA in a way that affects transcriptional activity at euchromatic loci, including the α-globin gene cluster. This interaction may be a result of alteration of the regional distribution of heterochromatin by the complex or of recruitment of transcription factors (directly or indirectly) that alter gene expression. ATRX function may be associated with its presence at one of its target nuclear locations (eg, heterochromatin, ribosomal DNA repeats, PML bodies) in addition to euchromatic sites. Potential points for interaction between ATRX and MDS, leading to a more severe hematologic phenotype than in ATR-X syndrome, include the multiprotein complex, of which ATRX is a part; transcription factors, whose binding to DNA is affected by the ATRX complex; and epigenetic modifications of histone-associated DNA, leading to alterations in local chromatin conformation.
53
what is important in chromatin maintenance and ATRX localization
AT-Hook2 domain in MeCP2
54
Opitz G/BBB syndrome
``` Optiz syndrome XR MID1 locus congenital malformation defective ventral midline devlopment ocular hypertelorism and hypospadias also: cleft lip and palate, laryngo-tracheal fistues, heart defefcts, imperforate anus, mental retardation ```
55
what kind of mutations can occur in MID1 gene
``` seen in opitz syndrome stop mutation frameshift mutaiton amino acid exchange insertion or deletion splicing mutation duplication ```
56
what does MID1 contain
phosphorylated serine and threonine residues
57
what specality does Optiz synrome have
Genetic Locus Heterogeneity can be XR or AR means similar symptoms, but different gene/mechanism
58
Congenital bilateral aplasia of vas defference
CFTR mutation absence of vasa deferntia, infertility
59
classic cystic fibrosis
non functional CFTR protein chronic sinusitis, severe chronic bacterial infections of airway, severe hepatobiliary disease, pancreatic exocrine insufficiency, meconium ileus at birth, sweat chloride value high, obstructive azosspermia
60
non classical CF
some functional CFTR protein, providing survival advance obstructive azoospermia!
61
Men infertility
abnormal embryologic development of teh epididymal duct and vas deferens- may be incomplete or absent congenital bilateral abasence of vas deferens 97-98% of men with CF
62
Infertility in women
lower fertility rate than non-CF women | viscid mucoid cervical secretions of low volume in women with CF
63
Pregnancy and CF
no significant difference in survival of women who become pregnant with CF compared to women who did not become pregnant (after adjusting for disease severity)
64
CFTR gene
``` cAMP-dependent chlorid-ion channel Expressed in the epithelial cells of the following organs: -respiratory system -sweat and salivary glands -pancreas -intestine -reproductive organs ```
65
respiratory and CF
too much chloride kept in cell, leads to dehydrated secretions, thick mucus instead of thin watery secretions
66
sweat gland and CF
high levels of NaCl not reabsorbed
67
Pancreas and CF
obstruct the digestive system and prevent pancreatic enzymes from reaching the small intestine
68
intestine and CF
presence of thickened mucus and lack of digestive enzymes, lead to increased risk for bowel obstruction, can sometimes be seen by ultrasound echogenic bowel (1-13% risk
69
CFTR mutations
more than 1000 identified found in more than 1% of CF chromosomes involed 72% of CF caucasian is homo- or hetrozygous for 8 mutations commen: missence AA deletion in F508
70
congenital bilateral absence of the vas deferens (CBAVD)
Vas deferens – carries sperm from the epididymis to the ejaculatory ducts Absence of vas occurs in 95% of males with CF CBAVD: distinct genetic disorder which overlaps with CF and causes infertility Noncoding region of CFTR gene involved: intron 8 with thymidine tracts (5T/7T/9T) 60-70% of men with CBAVD carry one mutation in the CFTR gene. 5T reduces the number of functional Cl- channels
71
Androgen insensitivity syndrome (AIS)
testicular feminization XR testosterone receptor mutation
72
polyglutamine disorders
Neurodegenerative disorders Different proteins Gain of function mutations Variable length Expansion Replicational slippage CAG repeats
73
polyalanine disorders
Developmental abnormalities Transcription factors Loss of function mutations Constant length Stable Uneven crossing over Non complete GCA, GCT, GCC, GCG repeats
74
Polyalanine disorder examples
Synpolydactyly type II HOXD13 Holoprosencephaly ZIC2 Hand-foot-genitals syndrome HOXA13 Blepharopimosis, ptosis, epicanthus inversus FOXL2

Y Sexual Genetics (10 decks)

Brainscape helps you reach your goals faster, through stronger study habits.
© 2025 Bold Learning Solutions. Terms and Conditions