Imprinting disorders Flashcards
What is the issue with gene imprinting with a pathological view?
- both maternal and paternal copies are present but only one is active
- no backup copy—a mutation in the active gene can lead to disease.
When does disease arise in imprinted genes?
- The only functional copy is mutated.
- Both copies are erroneously silenced, leading to a complete loss of gene function.
What is Beckwith-Wiedemann Syndrome (BWS) and its symptoms?
- A pediatric overgrowth disorder associated with an increased risk of tumor development.
Symptoms vary but include:
- Macrosomia (large body size)
- Organomegaly (enlarged organs)
- Abdominal wall defects
- By adulthood, growth abnormalities typically normalize.
What is the genetic basis of BWS?
- Linked to IGF-II (Insulin-like Growth Factor 2), an imprinted gene that is normally only expressed from the paternal allele.
What did the familial study in South Africa show about BWS?
- Showed BWS recurring in the same family tree, unusual for a rare disorder.
- Mutation originated in the grandfather, who passed on an imprinting defect to his grandchildren.
- Provided key evidence that BWS is an imprinting disorder rather than a classical Mendelian inheritance pattern.
What are the key features of Prader-Willi Syndrome (PWS)?
- Obesity
- Behavioral & cognitive impairments
- Underdeveloped sexual characteristics
What is the genetic mechanism of PWS?
Loss of paternal gene function in the PW critical region
What are the key features of Angelman syndrome (AS)?
- severe developmental delays
- ataxia, epilepsy
- characteristic “happy” demeanour
What is the genetic mechanism of AS?
Loss of maternal gene function in the AS critical region
What are the main genetic causes of PWS?
-70% – Paternal deletion of the Prader-Willi region (15q11-q13).
- 25% – Uniparental disomy (UPD) (two maternal copies, both silenced).
**This likely results from trisomy rescue, where an extra chromosome was lost, but the remaining pair came from the mother.
What are the other genetic causes of PWS?
- Mutation in the imprinting control region – No signal to remove imprinting marks, preventing gene activation.
- Chromosomal translocation – Misplaced regulatory sequences cause incorrect imprinting patterns.
**Can reduce fertility due to improper chromosomal pairing during meiosis.
What is the main therapeutic goal for PWS treatment?
Reactivate the silenced maternal genes since the paternal ones are missing.
How is CRISPR-based gene activation a strategy for PWS treatment?
- Uses Cas9 modified to activate transcription instead of cutting DNA.
- Targets the maternal chromosome to remove silencing.
- Can also alter methylation patterns by recruiting histone-modifying enzymes.
How does targeting the antisense transcript act as a therapeutic treatment for PWS?
- Some imprinted genes require antisense RNAs to maintain silencing.
- Downregulating Air RNA could allow genes on the maternal chromosome to be expressed.
How can topoisomerase inhibitors act as a therapeutic treatment for PWS?
- Can unlock chromatin structure, facilitating gene activation on the maternal chromosome.
How can gene replacement therapy act as a therapeutic treatment for PWS?
- AAV (Adeno-Associated Virus) vectors deliver functional copies of the missing genes.
How can metabolic interventions act as a therapeutic treatment for PWS symptoms?
- Introducing Brain-Derived Neurotrophic Factor (BDNF) into the hypothalamus may help regulate energy balance and appetite.
How can ShRNA/AAV9 Therapy
act as a therapeutic treatment for PWS?
- Targets EHMT2, a chromatin remodeler that contributes to gene silencing.
**Concern: EHMT2 has multiple functions, and silencing it may have unintended consequences.
What are the key challenges in gene therapy for PWS?
- Different genetic causes require different approaches.
- Target specificity is crucial to avoid off-target effects.
- Long-term safety & effectiveness need to be established before clinical use.
