Epigenetics and disease Flashcards
Angelman syndrome
Developmental delay
Severe speech impairment
Microcephaly
Can be caused by chromosomal deletion or uniparental disomy
Prader-Willi syndrome
Hypotonia (low muscle tone)
Insatiable appetite leading to obesity
Short stature
Compulsive behaviour
Caused by chromosomal deletion or uniparental disomy
PWS/AS chromosome deletion
15q11-13 deleted (4Mbp region)
If deleted chromosome is inherited from the father, this leads to PWS
If inherited from the mother, this leads to AS
Genomic imprinting in PWS/AS
On both chromosomes, the AS (paternal) and PW (maternal) genes are switched off through imprinting
If paternal chromosome is deleted, this leaves only the AS gene on the maternal chromosome. Lack of PW gene leads to PWS
If maternal chromosome is deleted, this leaves only PW gene on the paternal chromosome. Lack of AS gene leads to AS
Cytosine methylation and imprinting
DNA methyltransferase adds methyl groups to cytosine within CpG
Methylation removed in primordial germ cells and renewed during meiosis
PWS/AS and uniparental disomy
Both c.15 inherited from the father. Paternal imprint on both chromosomes (AS gene off). Leads to AS as equivalent to deletion on maternal chromosome
Both c.15 from mother. Maternal imprint on both chromosomes (PW off). Leads to PWS
Normal karyotypes/FISH
Bisulfite treatment
Methylation specific PCR
Sodium metabisulfite deaminates cytosines to uracil. Methylation stops sodium metabisulfite.
Different primers used based on methylation status
UBE3A
Loss of expression in the brain causes AS
Only imprinted (paternally) in neurons in the brain
Codes for protein turnover enzyme
Encodes E3 ubiquitin ligase which targets proteins such as p53
PWS gene
Small deletions in SNRPN (maternally imprinted). Codes for small nuclear ribonucleoprotein (may have role in RNA processing)
Also small nuclear RNA genes within introns of SNRPN
SNRPN imprinting centre
Controls expression of genes on the paternal chromosome
If methylated (maternal), SNRPN is not transcribed and other genes are not activated. UBE3A is transcribed
X inactivation
Females are mosaics of clones with maternal or paternal X active
xist lncRNA coats inactive X and recruits silencing factors (DNA methyltransferases)
In carriers for X-linked diseases, half the cells will lack the normal gene
Thrifty phenotype
Epigenetic adaptation to adverse environment
Child not adapted to plentiful resources
Increased risk of metabolic syndrome
S-adenosylmethionine needed for methylation and requires dietary folate
ICF syndrome
Defect in DNMT3B DNA methyltransferase leading to hypomethylation
Interferes with lymphocyte generation and activation
Characterised by immunodeficiency and persistent infections
Class three, four and five AS
Class one deletion
Class two disomy
Class three have no mutations or disomy, but abnormal methylation of maternal c.15
Class four patients have mutations within UBE3A
Class 5 patients have the AS phenotype but no c.15 abnormalities
