Landsberger: Lecture XXIII Flashcards
Methylation Associated Pathologies
What are the main mechanisms in which defects in DNA methylation can cause human disorders?
damages on DNA: cause tumors or genetic disorders
aberrant silencing of gene expression: causes genetic disorders (RTT, ICF) *aberrant means large number of genes are affected
aberrant expression of specific genes: cancer
diseases associated with imprinting Beckwith-Wiederman syndrome, Angelman syndrome (genes that are not usually expressed become expressed)
What is Rett Syndrome (RTT)?
genetic and progressive neurological disorder, which is rare as it only occurs in 1/6,000 humans
mainly in girls1st cause of severe intellectual disability in girls
What are some features associated with RTT/
severe ID
loss of expressive language
purposeful hand use
apraxia
breathing abnormalities
epilepsy
hypotonia
scoliosis
constipation
osteoporosis
bruxism
minor heart problems
What is RTT linked to?
X chromosome since the pathology mainly affects females & it is sporadic
caused by McCP2
What is MeCP2?
reader of DNA methylation that brings histone acetylases on DNA → transcriptional repressor that binds methylated DNA and silences gene expression reading methylated CpGs without sequence specificity
What does MeCP2 do in neurons?
functions as a chromatin condensing factor
What other gene has been linked to RTT?
CDKL5 (kinase ubiquitously expressed and the cause for an independent genetic disorder)
WHat other disorders can a mutation in MeCP2 cause?
RTT in females
neurological disorder in males
neonatal encephalotomy
Klinefelter condition where 1/2 MeCP2 alleles located on the X chromosome is mutant
What are loss of function mutations?
autism
Angelman like syndrome
X-linked mental retardation
learning disabilites
schitzophrenia
What are gain of function mutations?
duplication of the wild type gene (usually in boys)
*now called MeCP2 duplication syndrome
What 2 functions can mutations on MeCP2 cause?
gain or loss of function
What happens when a boy has a MeCP2 duplication syndrome disorder?
they have 2 or 3 copies of the wild gene (more copies increases severity)
usually die due to food getting stuck in the lungs
What is the clinical severity of RTT affected by?
X activation patterns (generally skewed)
MeCP2 mutations
presence of modifier genes
What is a problem with the null mice that are being used to study RTT?
the studies are being performed in males, but we cannot propose a clinical trial without testing a females (which is difficult since females respond diversely to drugs due to hormones)
What is MeCP2 required for?
everything in our brain, neurons and astrocytes
What goes on in the brain of the mice depleted of MeCP2?
there is a reduced volumed believed to be caused by neurons that do not contain MeCP2, which are smaller in the soma, less arborized, and have less spine in synaptic contacts
*this leads to a brain with the number of cells that are the same as a normal one, but everything has higher densities and leads to a smaller brain
What kind of disorder is RTT?
synaptogenesis disorder
there are less contacts so networks are not functioning properly
Why did Adrian bird inject tamoxifen into mice that lacked MeCP2?
in order to remove the stop codon and reactivate the endogenous gene → disorder is reversed in mice
How can we treat MeCP2 mutations in humans?
augmentative gene therapy or protein therapies, the conventional gene therapies
What are some problems with treating MeCP2 with augmentative gene therapy or protein therapies?
it is hard to get good viruses with good diffusions in the brain and be able to control dosage levels
there is general toxicity of the high dosage of MeCP2 that the virus could induce
What is MePC2 relevant for?
wildtype neurons and astrocytes
What exactly is Rett syndrome?
a disorder in which the lack of an epigenetic reader causes gene expression to be affected
*probably caused by a subtle activation or deactivation of different genes
**dominant disorder
What does ICF syndrome stand for?
immunodeficiency, centromere instability, and facial anomalies syndrome
What is ICF syndrome?
genetic recessive disorder where the mutated gene is mainly DNMT3B (50% of patients)
How can we diagnose patients with ICF syndrome?
have lots of infections due to terrible immunity
blood test is performed and shows aberrant chromosome shape
patients usually only survive to 10 years
The bottom line is we are going to get ICF if the DNMT3B is not ____
properly targeted on the right region of the genome or if the protein is not functining in a proper way
What are 2 contradictory features usually found in cancer?
hypomethylation and hypermethylation
What does hypomethylation affect?
regions where methylation mostly occurs (ones relevent for genome defense: transposons, viruses, repetitive elements)
What can hypomethylation do?
induce activation (dangerous for genome stability)
activate sequences (start to jump and produce viruses)
What kind of genome do cancer cells need?
unstable genome
What are the genes that are usually hypermethylated?
tumor supressor genes
Why is the pattern of methylation in tumor suppressor genes important?
helps us discriminate different kinds of cancers
helps us see the progression and see how much the cancer is advancing
