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BBD: Imprinting Disorders
Terms in this set (33)
What can placental defects lead to?
overgrowth or undergrowth of fetus
What can neurological defects lead to?
cognitive problems and developmental problems
What are some syndromes caused by imprinting disorders (neurological)?
Prader Willi syndrome and Angelman's syndrome
What are some syndromes caused by imprinting disorders (growth)?
Beckwith-Wiedemann and Silver-Russell syndromes
How does epigenetic silencing occur?
In the region 15Q 11.2 to 13 there is a gorup of genes that re differentially imprinted in the brain. During oogenesis, an imprinting center (promoter region for genes that follow) is methylated on the maternal chromosome. This methylation inhibits transcription of these genes of the maternal chromosome
Paternal Chromosome 15
Paternal chromosome is not methylated at imprinting center meaning that genes that are silenced on maternal chromosome are expressed from paternal only
What are the genes on the maternal chromosome that must be active in the brain?
This gene codes for ubiquitin protein ligase which functions in the proteasome system by ligating ubiquitin to target proteins and initiating degradation
codes for cation transport ATPase, which may have a Mg binding function and could be involved in phospholipid bilayer organization
What are the genes silenced on the maternal chromosome that must be active on the paternal chromosome?
a bi-cistronic gene encoding a spliceosome protein, and another protein of undetermined function. The SNURF gene has an imprinting center that regulate the expression of UBE3A-AS
What deletions result in no expression of UBE3A and ATP10A?
BP1 or 2 to BP3, 4 or 5
What does Angelman's syndrome result from
Deletion or mutation in UBE3A and ATP10A on the maternal chromosome resulting in non-functional ubiquitin protein ligase
codes for anti-sense RNA that blocks expression of UBE3A on the paternal chromosome
What does Prader-Willi syndrome result from?
- A deletion on the paternal chromosome resulting in no expression of SNURF-SNRPN and UBE3-AS
- No gene products from these genes are produced because silenced in maternal
What are some genetic imprinting changes that result in PWS?
1) Deletion of certain genes on the parental Ch 15 causes most cases
2) Uniparental disomy causes most of the rest. Imprinting center defect occurs when there is a maternal methylation pattern on the paternal chromosome
3) Microdeletions in the imprinting center, although not common, can occur; can lead to paternal chromosome being imprinted int he same manner as maternal --> genes silenced
How can uniparental disomy cause PWS and Angelmans?
- if a child inherits two copies of the maternal chromosome then no SNURF-SNRPN or snoRNA's --> PWS
- If a child inherits two copies of the paternal chromosomes no UBE3A expressed --> Angelman's
True or False: A translocation of genetic material from the maternal to paternal chromosome in the imprinting centre region results in Angelman's
False. The child develops PWS
What are the three causes of Angelman's?
1. Deletion of UBE3A and ATP10A on the maternal chromosome (75%)
2. Mutations in UBE3A (20%)
3. Mutations in imprinting center (5%)
What does the lack of UBE3A protein in Angelman's syndrome result in?
Results in the accumulation in neurons of proteins that should have been degraded but weren't --> protein aggregation disease
What are some proteins affected in Angelman's?
- Guanine exchange factor --> causes reduced dendritic spine formation in neurons
- Protein associated with the cytoskeleton --> participates in trafficking of AMPA and NMDA receptors
- Sometimes GABA genes lost and GABA receptors affected --> epilepsy
What are some characteristics of Angelman's syndrome?
- short attention span
- hyperactive but not aggressive
- fascination with water
- intellectual and developmental delays
- sleep disturbances
- abnormal EEG's
- many have seizures
- speech development impaired
- laugh frequently
- hypotonia turning into hypertonia of the limbs (unsteadiness of gait and ataxia)
- jerky puppet like movement of the limbs
- If affects OCA2 gene --> oculocutaneous albinism
- life span normal
- incidence is 1/25,000 births
What are the three main causes for PWS?
1. Deletion of some of the paternally active genes on Ch 15
2. Child inherits 2 maternal chromosomes (uniparental disomy)
3. mutation in imprinting center
True or False: Angelman's syndrome problems show up before birth whereas PWS doesn't develop problems until later on
False. PWS before birth, AS 6 months
In PWS, which problems can be seen before birth?
- hypotonia causing decreased fetal movement
- decreased birth weight
- abnormal position at birth (breech)
What are the characteristics of PWS?
- hypotonia --> causes lethargy, poor relexes, poor suck
- failure to thrive in early months but resolves around 9 months
- delayed motor development (double normal age)
- mild intellectual disability
- 3-4 years appetite increases dramatically and children gain weight
- by 8 they have developed hyperphagia accompanied by food seeking and lack of satiety
- Ghrelin levels in stomach are high
- loss of lean muscle mass
- facial features --> narrow bifrontal diameter, narrow nasal bridge, downturned corners of mouth
- Hypopigmentation of hair, eyes and skin if cause is deletion in OCA2 gene
- Temper tantrums, very stubborn, manipulative behaviour, compulsivity and difficulty with change
- sleep abnormalities
- signs of autism
- genital hypoplasia and hypogonadism --> delayed puberty and infertility
- short stature and deficient in growth hormone
- Often develop Type II Diabetes
- Changes in structure of brain --> bigger ventricles, decreased volume of brain tissue in some areas
What is the risk of PWS to subsequent children?
- depends on the genetic mechanism that resulted int eh absence of expression of paternal 15q11.2-q13 region.
- less than 1% if deletion or uniparental disomy
- 50% if imprinting defect
- 25% if parental chromosomal translocation present
Initially, how was imprinting disorders tested for?
Using a methylation specific restriction enzyme, PCR and southern blotting. This could determine if the methylation pattern was abnormal but not the cause
What is used to test imprinting disorders now?
- Bisulphite sequence analysis
- Fluorescence in situ hybridization (FISH)
- Methylation specific multiplex ligation-dependent probe amplification (MS-MLPA)
Bisulphite sequence analysis
DNA is treated to replace all unmethylated cytosine nucleotides with thymine nucleotides.
FISH with SNRPN probe
allowed for distinction to be made between a deletion in a certain region, uniparental disomy and an imprinting center deletion
- multiplex polymerase chain reaction PCR-based method that an detect changes in the gene copy number status, DNA methylation, and point mutations simultaneously
- MLPA probes recognize target sequences of only 50 to 100 nucleotides in length. This makes it possible to use MLPA even on highly fragmented DNA, and allows the detection of small deletions encompassing only a single exon
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