14. Structural abnormalities of X chromosome Flashcards
What is isochromosome X?
2 copies of the long arm of the X chr - unbalanced rearrangement
What is i(Xq) associated with?
Turner syndrome due to loss of SHOX at PAR
Also in patients with variant of Klinefelter syndrome - 47,X,i(Xq),Y
Why is an isochromosome for Xp not viable?
XIST would be absent - disomy for genes on Xp
What is a ring chromosome?
Chr whose ends have fused together - range in size depending on amount of material lost from p and q arms
What phenotype is associated with rX that includes XIST?
Phenotype varies from Turner syndrome to normal depending on amount of X chr lost
Selective X-inactivation
Cells with normal X inactivated are nullsomic for parts of X chr that are missing from rX
What phenotype is associated with rX without XIST? Why?
Severe phenotype
Fail to undergo X inactivation - functional disomy for genes retained on ring
Often small rings as functional disomy only tolerated for small number of genes
What are the PARs?
What is their function?
Short regions of homology between X & Y - contain genes present on both
Allow X & Y to pair & segregate during meiosis in males
Escape inactivation as dosage compensation not required
What key gene is located in the PAR? What is its role?
SHOX - important TF involved in formation of body structure in early embryonic development
Why are PARs expressed from both Xs in females?
PARs escape X inactivation
What is the most common X/Y translocation?
t(X;Y)(p22;q11)
What phenotype is associated with deletions in the Xp22.3 region?
Icthyosis (STS)
Hypogonadism, ID (KAL1)
Short stature (SHOX)
What phenotype is associated with deletions in the Xp11.22 region?
HUWE1, CLCN5 - associated with ID
What phenotype is associated with MECP2 duplication syndrome?
Moderate/severe ID
Immune abnormalities if IRAK1 is duplicated
Seen exclusively in males, females unaffected due to selective X inactivation
What is the result of translocations with breakpoints in Xq13-22?
Ovarian disorders ranging from premature ovarian insufficiency to primary amenorrhea.
What is the effect of a balanced X-autosome translocation in females?
Preferential (skewed) inactivation of normal X
Functional balance achieved using both parts of the X in the translocated chromosome as the active X
Breakpoints in Xq13-22 cause ovarian disorders
What is the effect of a balanced X:autosome translocation in males?
Disruption of the X-Y bivalent at meiosis –> Spermatogenic arrest and infertility
What are the potential consequences of skewed X inactivation in patient with a balanced X;autosome translocation?
Normal X not preferentially silenced
Monosomy of some autosomal genes (due to the spread of X inactivation)
Functional disomy of other X chromosome genes
XLR disorder (e.g. DMD) may manifest due to skewing
What phenotype is associated with balanced X-autosome translocations in females?
Usually normal
Ovarian dysfunction if breakpoints are in critical region - Xq13-22
What is the purpose of X-inactivation?
How does it occur?
Mechanism for gene dosage compensation
Equalises X chromosome gene expression between males and females
Random transcriptional silencing of either maternal or paternal X chromosome
When does X inactivation occur?
As cells differentiate in late blastula stage
Pattern of X inactivation inherited stably in daughter cells
Describe the structure of the inactive X
Highly condensed, heterochromatic state
Visualised as a Barr body
Describe the mechanism of X inactivation
Initiated at XIC
XIST is a lncRNA transcribed from inactive X only - acts in cis
XIST spreads from XIC, recruits polycomb proteins, coats X chr –> DNA methylation and histone acetylation
What is the role of Tsix?
Transcribed from antisense strand of XIST - represses XIST expression through DNA methylation and histone acetylation
How do XIST and Tsix regulate inactivation?
Prior to inactivation, both Xs weakly express XIST and Tsix
At inactivation, future inactive X ceases to produce Tsix and XIST expression increases
XIST is repressed on active X by methylation of promoter
What is the effect of random X inactivation on XLD disorders?
Trait is less severe in females as 50% of cells with pathogenic X are inactivated
Female more severely affected due to non-random/skewed X inactivation due to variants in Xist or Tsix
How can skewed X inactivation be tested for?
Most commonly HUMARA assay
gDNA digested with methylation-specific enzyme - digests unmethylated allele only
Amplification of CAG STR in AR gene - only methylated allele is amplified
