Epigenetics & Imprinting Disorders

Question 1

Define epigenetics

Answer 1

the study of changes in organisms caused by modification of gene expression rather than alteration of the genetic code itself

Question 2

DNMTs

Answer 2

De Novo MethylTransferases:
- Catalyzes transfer of a methyl group from S-adenyl methionine (SAM) to the 5th carbon of cytosine to form 5-methylcytosine

Question 3

Dnmt3a and Dnmt3b function

Answer 3

establish new methylation patterns on unmodified DNA

Question 4

Differentiate the Epigenetic tools: Writers, Readers, and Erasers

Answer 4

Writers: introduce modifications on DNA and histone tails

Readers: binds to modifications using specialized domains

Erasers: remove modifications introduced by the writers

Question 5

Somatic vs Germline changes

Answer 5

Somatic mutations: not transmitted to progeny

Germline: can be transmitted to some or all progeny

Question 6

Genomic Imprinting

Answer 6

• only one copy of a gene in an individual (maternal or paternal) is expressed, while the other copy is silenced (imprinted genes)

NOTE: maternal and paternal imprints are erased in Premature germ cells, but re-expressed in mature germ cells to offspring

Question 7

Imprinting Disorders in Human Health

Answer 7

1. Uni parental Disomy
2. Deletion
3. Epimutation
4. Point Mutation

NOTE: methylation defect

Question 8

Beckwith-Weidmann Syndrome (BWS) Phenotype

Answer 8

• macroscomia/ hemihyperplasia/ macroglossia
• neonatal hypoglycemia
• ear crease/ pits
• childhood cancers

Question 9

Molecular genetics of BWS

Answer 9

Beckwith-Wiedmann Syndrome:

• loss of methylation at MATERNAL IC2 (imprinting control centre 2 epimutation) = 50%
• paternal UPD = 20%
• CDKN1C mutation
• inversion or translocation at chromosome 11

Question 10

Silver-Russel Syndrome Phenotype

Answer 10

• Asymmetric growth (relatively large head, small body)
• Post-natal growth failure
• Triangular face (prominent forehead)
• 5th finger curved inward
• Feeding difficulties
• Café-au-lait macules (birthmarks)

Question 11

Molecular Genetics of SRS

Answer 11

Silver-Russell Syndrome:
- 11p15.5 ICR1 hypomethylation (paternal)
- maternal UPD 11, UPD 7
- CDKN1C, IGF2, PLAG1, HMGA2 gene mutations

Question 12

Prader Willi Syndrome Phenotype

Answer 12

• hypotonia (low muscle tone, floppy baby)
• hyperphagia = obesity
• Infertility
• Short stature

Question 13

Molecular Genetics of PWS

Answer 13

Prader Willi Syndrome:
- paternal 15q11.2-q13 deletion
- maternal UPD 15

Question 14

Angelman Syndrome Phenotype

Answer 14

• Severe developmental delay, intellectual disability, speech impairment
• Wide, gait ataxia
• (frequent laughing, smiling, excitability)
• Seizures
• Microcephaly (small head size) with onset after birth

Question 15

Molecular Genetics of Angelman Syndrome

Answer 15

• Paternal UPD15
• UBE3A gene mutation
• maternal deletion of 15q11.2-q13

Question 16

Disruption of Writers

Answer 16

• variants or deletions of EHMT1 gene (Euchromatin Histone Lysine Methyltransferase 1) = Kleefsta Syndrome

Question 17

Disruption of Readers

Answer 17

Variants in MECP2 (Methyl CpG binding protein 2) = Rhett syndrome

Question 18

Dnmt1 function

Answer 18

copies the DNA methylation pattern from the parental DNA strand onto the newly synthesized daughter strand during DNA replication

Question 19

3 DNMTs important for embryological development

Answer 19

• Dnmt3a
• Dnmt3b
• Dnmt1

Question 20

Imprinting Control Regions

Answer 20

• gene expression is controlled by imprinting control regions (ICR)
• done through methylation