Genomic Imprinting

Question 1

What is Prader- Willi syndrome caused by?

Answer 1

Most people with this disorder have a microdeletion in the long arm of chromosome 15

Question 2

What are some clinical manifestations of Prader- Willi syndrome during infancy?

Answer 2

Hypotonia
Feeding difficulties
Hypogonadism

Question 3

What are some clinical manifestations of Prader- Willi syndrome during childhood?

Answer 3

Uncontrollable appetite; obesity

Moderate intellectual disability

Question 4

What is Angelman syndrome caused by?

Answer 4

microdeletion of exactly the same region of chromosomes 15 as Prader-Willi

Question 5

What are some clinical manifestations of Angolan syndrome?

Answer 5

growth delay, spastic, ataxic movements, and high risk of seizures, and an intellectual disability that is more severe than in Prader-Willi syndrome

Question 6

What are some types of epigenetic regulation mechanisms?

Answer 6

DNA methylation in tissue-specific regulation of gene expression (specificity may be dynamic)

X inactivation (heritable from cell to cell but not from one generation to the next)

Genomic imprinting (parent of origin effects transmitted through gametes; intergenerational effect)

Question 7

Are epigenetic effects heritable?

Answer 7

Yes, but they are reversible

Question 8

Explain genetic imprinting.

Answer 8

For a small subset of genes, it is normal for that gene to have one methylation pattern in male gametes and a different methylation pattern in female gametes. The differences in methylation lead to differential expression of the paternally- and maternally-derived copies of the same gene.

For these genes, this is normal.

Question 9

What are some examples of imprinted Genes on Chromosome 11 and their imprinting patterns.

Answer 9

IGF2 (insulin-like growth factor type 2), chromosome 11p15
Paternal copy expressed (biallelic expression-aka imprinting effect escaped- in some tissues)

KVLQT1 (potassium channel gene mutated in long QT syndrome), chromosome 11p15
Maternal copy expressed (biallelic expression in heart)

We have two perfectly normal and potentially functional copies of these two genes, but imprinting means that only one copy is expressed according to specific parent-of-origin patterns.

Question 10

What are some examples of imprinted Genes on Chromosome 15q and their imprinting patterns.

Answer 10

SNRPN (small nuclear ribonucleoprotein polypeptide N), chromosome 15q12
Paternal copy expressed

UBE3A (ubiquitin protein ligase 3), chromosome 15q12
Maternal copy expressed in brain; both copies expressed elsewhere

Question 11

What controls imprinting?

Answer 11

an Imprinting Control Region (ICR) on the chromosome

Question 12

When does the ICR set the imprint?

Answer 12

during gametogenesis. Subsequent to fertilization, the gene expression pattern from the gametes plays out through development and adulthood

Question 13

Of the ~20,000 genes in the human genome, approximately how many are imprinted?

Answer 13

~150 genes are imprinted

Question 14

T or F. imprinted genes are scattered throughout the genome and affect both maternal and paternal alleles

Answer 14

T

Question 15

Outline the steps of the imprinting cycle

Answer 15

The sex-specific imprint is put in place during gametogenesis. At fertilization, each embryo gets a maternal complement and a paternal complement, and the gene-specific patterns from each gamete are maintained throughout development and in the somatic tissues of that person. However, in their gonads, the imprint is erased, and then it is reset according to the sex of that prospective parent.

Question 16

What is the main basis of genetic imprinting and its role in genetic disease?

Answer 16

If it is the normal situation to have only one active allele (because the other allele is silenced by normal genomic imprinting), then it follows that anything that causes loss of function of the allele that is intended to be ‘ON’ will eliminate all gene function. Loss of critical gene function may cause disease.

Question 17

What is Prader-WIlli Syndrome caused by in relation to imprinting?

Answer 17

The critical region for the paternally non-imprinted gene that prevents PWS is flanked by LCRs that are susceptible to unequal crossover. Typically, unequal crossover causes a ~4-6Mb deletion that includes the critical region

Angelman syndrome is caused by the same thing on the maternal homolog of chromosome 15

Question 18

Are the critical regions involved in PWS and AS the same?

Answer 18

No, the critical regions are distinct. However, BOTH just happen to be contained within the segment that is prone to deletion by unequal crossing over (on their respective homologs)

Question 19

What are some of the other causes of PWS?

Answer 19

70% paternal deletion (microdeletion)
~28% maternal uniparental disomy
~2% mutation of the imprinting center- during spermatogenesis, SNRPN fails to get “turned on”.

Take home message- Patients with PWS have no functional paternal contribution of the critical region. By whatever mechanism, they are not producing SNRPN.

Question 20

What is maternal uniparental disomy?

Answer 20

In this situation, the patient has two structurally normal copies of chromosome 15, but both copies are of maternal origin

Question 21

What are the causes of AS?

Answer 21

70% maternal deletion (microdeletion)

> 5% paternal uniparental disomy

Question 22

Are most cases of PWS and AS de novo or heritable?

Answer 22

de novo. The severity of these two conditions makes it very unlikely that affected individuals will reproduce. Thus, it follows that most affected individuals are the result of a de novo event. This is in keeping with mutation-selection equilibrium

Question 23

How can Uniparental Disomy occur?

Answer 23

“trisomy rescue”. The first error is meiotic nondisjunction, giving rise to trisomy in the conceptus (fairly common). As a specific example, age-related risk of maternal nondisjunction, leading to trisomy 15, is common. But it will always result in miscarriage, as trisomy 15 is a lethal condition, and indeed, the vast majority of trisomy 15 pregnancies end in miscarriage.

The very rare exception is when the following occurs as a second, independent, presumably random, error. Sometime early in development (e.g. morula), one cell sustains a mitotic nondisjunction whereby one of the extra copies of chromosome 15 is lost. In that cell and its descendants, a “normal” chromosome complement has been restored. This cell lineage has acquired a selective advantage. It has the potential to continue to divide, differentiate, and form an embryo and fetus. It can be expected to outcompete its trisomy 15 counterparts