Genomic imprinting Flashcards
Define imprinting.
The process by which one parental allele is preferentially silenced according to its parental origin. Over 40 genomic regions are known to be imprinted, and more than half of imprinted genes are involved in pre- and post-natal growth.
What is the conflict hypothesis? (Haig and Graham, 1991)
Paternally expressed genes promote growth, maternally expressed genes suppress growth. These genes are normally balanced, but imbalances can lead to imprinting disorders.
Explain how imprinting occurs during development.
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Abnormalities of imprinting typically occur through which 3 mechanisms?
- Chromosome rearrangements - deletions and duplications. 2. Aberrant methylation pattern. 3. Uniparental disomy.
What is uniparental disomy?
Inheritance of both copies of one particular chromosome from a single parent. Occurs through two different mechanisms following a non-disjunction event during meiosis: HETERODISOMY: parent passes on one copy of each chromosome homolog (non-disjunction in meiosis I). ISODISOMY: parent passes on two copies of the same chromosome (non-disjunction in meiosis II or postzygotic chromosome duplication). In both cases, trisomic rescue removes the single homolog from one parent, leaving two homologs from a single parent.
Give 5 characteristic features of Beckwith-Wiedemann syndrome.
- Characterised by overgrowth
- Abdominal wall defects (omphalocoele, umbilical hernia, diastasis recti)
- Visceromegaly
- Macroglossia
- Earlobe creases/pits
- May present with hemihypertrophy - overgrowth confined to one side of body
- Other complications - urogenetial abnormalities, neonatal hypoglycaemia, embryonal tumours
Explain the molecular basis of Beckwith-Wiedemann syndrome, and how these molecular changes can arise.
Beckwith-Wiedemann syndrome may be caused by epimutations (abnormal changes in methylation) at 11p15 or paternal UPD 11. The molecular cause may be:
- Abnormally increased expression of IGF2 (insulin-like growth factor 2)
- Abnormally reduced expression of cell cycle inhibitor CDKN1C
Describe the clinical characteristics of Silver-Russell syndrome.
- Opposite of Beckwith-Wiedemann - characterised by reduced growth
- Intrauterine and postnatal growth retardation
- Relative macrocephaly
- Small triangular face
- Prominent forehead
- 5th finger clinodactyly
- Asymmetry of head, limbs and trunk
Describe the molecular basis of Silver-Russell syndrome.
- >50% caused by abnormalities at 11p15, primarily hypomethylation at paternal H19DMR
- 5-10% caused by maternal UPD 7
Summarise the genetic alterations that result in Beckwith-Wiedemann syndrome and Silver-Russell syndrome.
Type of alteration in 11p15
Frequency in BWS
Frequency in SRS
UPD of 11p15
10-20%
-
Paternal/maternal duplications
1-2%
1%?
Epimutations in ICR1 (IGF2/H19)
2-10%
30-55%
Epimutations in ICR2 (KvDMR)
50% (sig dec risk of tumour)
<1%
Describe the clinical features of Angelman syndrome.
- Severe cognitive impairment
- Receptive and non-verbal skills better than verbal
- Ataxia
- Unique behaviour: short attention span; easily excitable; happy disposition
- Microcephaly
- Seizures
- Sleep disturbances
Describe the clinical features of Prader-Willi syndrome
Babies:
- Central hypotonia
- Feeding difficulties
- Failure to thrive
Ages 1-6:
- Hyperphagia
- Rapid weight gain with strikingly fat limbs
- Truncal obesity
- Small hands and feet
- Short stature
- Small genitalia in males
- Moderate-severe learning difficulties - avg IQ 60
- 80% have behavioural problems
- Hypogonadotrophic hypogonadism
Describe the different molecular causes of Angelman syndrome.
- 70% interstitial deletions of maternal PWASCR
- 2-5% paternal UPD 15
- 2-5% imprinting defect
- 20% UBE3A (missense) mutation
Describe the different molecular causes of Prader-Willi syndrome.
- 75% deleted PWASCR
- 25% maternal UPD
- 1% imprinting defect (epimutation)
Describe the hypothesised causes of imprinting disorders in assisted reproductive technology (ART).
- May be related to culture medium
- May be related to prolongation of in vitro culture times
- May be related to infertility and so ovarian hyperstimulation may be responsible rather than IVF
