Imprinting Disease

Question 1

What assumptions are made in Medelian Inheritance about each parent’s genetic contribution and expression of parental gene copies?

Answer 1

• Each parents contribution is equal (except for male sex chromosomes)
• Children are expected to express equally (biallelic expression)

Question 2

What are the symptoms of Prader-Willi Syndrome?

- What causes it?

Answer 2

• Hypotonia
• Poor Feeding
• Develop insatiable appetite during childhood
• Microdeletion in long arm of chromosome 15

Question 3

What are symptoms of Angelman Syndrome?

- What causes it?

Answer 3

• Spasticity and Seizure
• Severe intellectual disability
• Growth retardation
• Microdeletion in long arm of chromosome 15

Question 4

What two disease result from deletions on chromosome 15, what explains the different manifestations of this syndrome?

Answer 4

• Prader-Willi and Angelman syndromes

- Manifestations differ on the basis of whether the maternally or paternally derived chromosome is lost.

Question 5

What are epigenetic Mechanisms?

Answer 5

• DNA modifications that are HERITABLE BUT REVERSIBLE (e.g. X - inactivation in females, gene deactivation through methylation)

Question 6

Imprinting?

Answer 6

• Small subset of genes where only the paternally or maternally derived genes copy is expressed.

Question 7

What is the consequence of imprinting?

Answer 7

• Differential (nonequivalent) gene expression that is dependent on parental origin that occurs NORMALLY

Question 8

What is the master control region of imprinting?

-When does it set the imprint?

Answer 8

Imprinting control region (ICR)

• Imprint set in gametogenesis

Question 9

In imprinting region if genes are turned on the the sperm, what happens to to egg?

Answer 9

The genes are turned off

Question 10

T or F: imprinting only happens in only a few genomic locations

Answer 10

False, imprinted genes are located throughout the genome

There are about 150 of them

Question 11

What is the imprinting cycle?

Answer 11

1. Imprint is put into place during gametogenesis (opposite genes will be activated in the sperm and egg)
2. That imprint is maintained in the offspring throughout developement and in somatic tissue
3. In the gonads the imprint is reset according to the sex of that prospective parent (genes that are not active in the parent may be turned on in the gamete and visa versa to get male specific and female specific gametes)

See 4.1 slide 13

Question 12

What will happen to all the paternal paterns in a females gametes?

Answer 12

• She will erase them and replace them with a female pattern

Question 13

What happens if you have a paternally imprinted gene and the maternal gene loses function?

Answer 13

• All gene function at that allele will be eliminated

Question 14

What is the result of unequal crossing over between LCRs (Low Copy Repeats) in PWS an AS?

Answer 14

It causes deletion of ~5 Mb segment that includes the critical regions

Question 15

What are PWS and AS and which parental homologues are deleted in each?

Answer 15

• Prader-Willi Syndrome - deletion of paternally-derived chromosome
• Angelman syndrome - deletion of maternally-derived chromosome

Question 16

In males which is turned on in male gemetogenesis SNRPN or UBE3A?

Answer 16

SNRPN, females turn on the UBE3A gene

Question 17

What low copy repeats underlie Prader-Willi and AS?

Answer 17

BP1, BP2, and BP3

Question 18

What are the 3 causes of PWS?

Answer 18

1. 70% paternal deletion (micodeletion)
2. 28% Maternal uniparental disomy (two maternal chromosomes, non from dad)
3. 2% mutation of the imprinting center (SNPRN is never turned on)

***COMMON TO ALL OF THESE IS THE ABSENCE OF 15q12 critical region, by lack of SNRPN production

Question 19

What is the common cause of ALL PWS?

Answer 19

No paternal contribution to 15q12 critical region

Question 20

What is the common cause of ALL AS?

Answer 20

No maternal contribution to 15q12 critical region

Question 21

What are some causes of AS?

Answer 21

• 70% maternal deletion (microdeletion)
• 5% parental uniparentla disomy (two from dad, non from mom)
• 5% mutation of the imprinting center
• 10% point mutations
• 10% unknown

Question 22

What is uniparental disomy?

Answer 22

you get the correct number of chromosomes but one homologous pair is strictly from one parent

Question 23

how is uniparental disomy caused?

Answer 23

• caused by 2 parental errors

Trisomy Rescue:
1. Meiotic nondisjuction giving rise to trisomy on conception

2. Morula (early developement) MITOTIC non-disjunction (loss of one of the trisomy chromosomes)
   - This cell line will outcompete the cell line with abnormal amount of genetic information

Question 24

What are the chances of that Uniparental disomy will accompany trisomy rescue?

Answer 24

1/3 because of the 3 chromosomes at that spot