Compiled from lecture notes, this is a condense but detailed summary of the sex chromosome l anomalies covered in BHCS3009 module. All the information (and more) is available in one place in a logical order, easy to search and use for revision.
Prenatal development
• Chromosome sex established at fertilisation
• At 6 weeks, 46XX and 46XY have same organs – undifferentiated gonads developed from genital ridges
lying on the side of interim kidneys
• Important to determine when looking at sex development disorders
• Steroidogenic factor gene (SF1) on chromosome 9 encodes a nuclear receptor associated with
hormone production
• Wilms tumour suppressor protein 1 (WT1) on chromosome 11p active in development of gonads and
kidneys
• 2 primitive ducts – male-like Wolffian ducts, female-like Mullerian ducts
• Externally, both embryos have genital tubercle and urogenital groove surrounded by folds and swelling
• Both male and female ducts, derived from mesonephrons, are present in a 6-week embryo
Male development and sex differentiation
• At 7 weeks, SRY gene on chromosome Yp produced protein testis-determining factor (TDF) – this
triggers inner part of gonadal ridges to develop into testis
• Other X-linked and autosomal genes necessary for differentiation of testis – e.g., SOX9 (homeobox)
gene on chromosome 17
• Foetal testis begin to secrete 2 hormones
o Anti-mullerian hormone (AMH) causes Mullerian ducts to regress – AMH in chromosome 19q
functions only in presence of Y chromosome, activity regulated by SF1 product
o Testosterone produced to maintain Wolffian ducts which form prostate gland, seminal vesicles
and vas deferens
o Dihydrotestosterone (DHT), derived from testosterone, organises shaping of external genitals
(conversion catalysed by 5-reductase – penis and scrotum formed
• SRY regulation in mouse model
o Epigenetic modifiers, transcription factors and kinases involved in SRY regulation
o Model assembles all known regulators into 3 modules, each converging on a single transcription
factor that binds SRY promoter (for normal functioning)
• Genome wide analysis
o Activation of SRY initiates testis development
o SRY is a transcription factor – a protein complex (including SRY) binds to a SOX9 enhancer
element
o SOX9 interactions with other elements causes male sex determination to occur and testis
development
o 4 patients with 46XX, testicular disorders who where SRY-negative
▪ Compared loss of heterozygosity (LOH) and CNV to normal female control data
▪ LOH induced 27 genes in 19 regions of 11 chromosomes
▪ CN loss included 55 genes in 13 regions of 10 chromosomes
▪ CN gain in 6 regions of 4 chromosomes, including upstream region of SOX3 located in
Xq27.1 (non-coding region)
▪ Likely that CN gain led to high expression of SOX3 causing testicular development,
despite no SRY
• Defects in testosterone synthesis
o Can have mutation at any stage of synthesis which is defective
o Variety of different sex developmental disorders depending on synthesis stage defect occurs
Female development and sex differentiation
, • Occurs in absence of male development
• Products of several genes causes parts of genital ridges to develop into ovaries at 12 weeks
• DAX1 plays key role – encodes nuclear hormone receptor related to SF1 and functions as anti-testis
gene by opposing effect of SRY
• Other X-linked and autosomal loci required
• 2 X chromosomes required for ovarian maintenance
• Wolffian ducts regress in absence of testosterone
• Mullerian ducts form female ducts, in absence of AMH
• Forward parts from fallopian tubes, end parts fuse to form uterus and vagina
• External genitalia fail to fuse and clitoris forms from genital tubercle and labia from surrounding
folds
• Undifferentiated gonads develop into ovaries in absence of normal SRY expression
• X chromosome inactivation
o Mary Lyon (1961) suggested hypothesis for dosage compensation regarding genes on X
chromosome
o In females, an X chromosome is randomly inactivated during embryogenesis – inactivation is
irreversible so same X chromosome is inactive in all daughter cells (i.e., all somatic cells)
o In some cells, maternal X is inactivated and in other cells paternal X is inactivated so females
are mosaic regarding active X chromosome
o Not all genes on inactive X chromosome are inactivated (genes escape)
o X inactivation controlled by X-inactivation specific transcript (XIST) gene which produces a
poly-adenylated RNA which acts to initiate cascade of events leading to inactivation
o Barr (1949) observed heterochromatin in nuclear periphery of many cells – correlates to
number of inactive X chromosome
o Buccal smears used to examine Barr bodies in infants with ambiguous genitals (now
replaced with FISH
▪ No Barr body = normal male, female with turner Syndrome (45X)
▪ 1 Barr body = normal female, 47XXY male
▪ 2+ Barr body = aneuploidy
o Only 1 active X chromosome per cell (no matter how many X chromosome there are)
o Methylation of Barr body
• Methylation inactivates X chromosome
• Methylation seen using immuno-FISH analysis
Sex chromosome anomalies – won’t be asked exam question on specific disorder, but could be asked to
give overview of main disorders with attention on Turner and Klinefelter syndrome
Y chromosome – phenotypically male
X chromosome – phenotypically female
Turner Syndrome – 45,X
• Liveborn incidence 1 in 5000 female births
• Ultrasound detect generalised oedema or swelling localised to neck
• Symptoms include
o Webbing of neck
o Under 5 foot tall (short statue)
o Normal intelligence
o SHOX gene haploinsufficiency
o Streak ovary results in primary amenorrhoea and infertility
o Coarctation of aorta in 15% of cases
• Diagnosis suggested in newborn by redundant neck skin and peripheral lymphoedema
The benefits of buying summaries with Stuvia:
Guaranteed quality through customer reviews
Stuvia customers have reviewed more than 700,000 summaries. This how you know that you are buying the best documents.
Quick and easy check-out
You can quickly pay through credit card or Stuvia-credit for the summaries. There is no membership needed.
Focus on what matters
Your fellow students write the study notes themselves, which is why the documents are always reliable and up-to-date. This ensures you quickly get to the core!
Frequently asked questions
What do I get when I buy this document?
You get a PDF, available immediately after your purchase. The purchased document is accessible anytime, anywhere and indefinitely through your profile.
Satisfaction guarantee: how does it work?
Our satisfaction guarantee ensures that you always find a study document that suits you well. You fill out a form, and our customer service team takes care of the rest.
Who am I buying these notes from?
Stuvia is a marketplace, so you are not buying this document from us, but from seller AH1984. Stuvia facilitates payment to the seller.
Will I be stuck with a subscription?
No, you only buy these notes for $13.17. You're not tied to anything after your purchase.
