Genomic imprinting

Question 1

What is genomic imprinting?

Answer 1

Genomic imprinting is a process where one of the alleles is transcriptionally inactive depending on the parent from whom it was inherited.

Question 2

What is the principle established by Mendel’s work with garden peas?

Answer 2

The phenotype is the same whether a given allele is inherited from the mother or the father.

Question 3

How many human genes are known to be imprinted?

Answer 3

At least 100 human genes are known to be imprinted.

Question 4

What is the function of the imprinting control region (ICR)?

Answer 4

The ICR sets the imprint according to the sex of the transmitting parent.

Question 5

What characterizes imprinted alleles?

Answer 5

Imprinted alleles tend to be heavily methylated.

Question 6

What is the effect of methylation on gene transcription?

Answer 6

Methylation inhibits the binding of proteins that promote transcription.

Question 7

What are the two syndromes associated with chromosome 15 deletions?

Answer 7

• Prader-Willi syndrome (PWS) * Angelman syndrome (AS)

Question 8

What features characterize Prader-Willi syndrome (PWS)?

Answer 8

• Short stature * Hypotonia * Small hands and feet * Obesity * Mild to moderate intellectual disability * Hypogonadism

Question 9

What features characterize Angelman syndrome (AS)?

Answer 9

• Severe intellectual disability * Seizures * Ataxic gait

Question 10

What genetic mechanism can lead to Prader-Willi syndrome and Angelman syndrome?

Answer 10

Uniparental disomy.

Question 11

What gene is responsible for Angelman syndrome?

Answer 11

UBE3A.

Question 12

What condition is characterized by growth retardation and small facial features?

Answer 12

Silver–Russell syndrome.

Question 13

What is the relationship between DMR1 and Silver-Russell syndrome?

Answer 13

Loss of methylation of DMR1 leads to down-regulation of IGF2 and diminished growth.

Question 14

What is anticipation in genetics?

Answer 14

A pattern where genetic diseases display an earlier age of onset and/or more severe expression in more recent generations.

Question 15

What is the genetic cause of myotonic dystrophy?

Answer 15

An expanded CTG trinucleotide repeat in the DMPK gene.

Question 16

What is the typical range of CTG repeats in unaffected individuals?

Answer 16

5 to 37 copies.

Question 17

How does the number of CTG repeats correlate with disease severity in myotonic dystrophy?

Answer 17

The number of repeats is strongly correlated with severity of the disease.

Question 18

What is a common feature of congenital myotonic dystrophy?

Answer 18

Large expansions of the CTG repeat are transmitted almost exclusively by females.

Question 19

What is the typical age of onset for myotonic dystrophy as repeat numbers increase?

Answer 19

The age of onset decreases as the number of repeats increases.

Question 20

What is myotonic dystrophy?

Answer 20

A genetic disorder characterized by muscle loss, cardiac arrhythmia, cataracts, and frontal balding

Myotonic dystrophy has two types: Type 1 (DM1) and Type 2 (DM2), each caused by different repeat expansions.

Question 21

What is the primary cause of anticipation in myotonic dystrophy?

Answer 21

Expansion of trinucleotide repeats

Anticipation refers to progressively earlier or more severe expression of a disease in more recent generations.

Question 22

What is the repeat sequence associated with myotonic dystrophy type 1?

Answer 22

CTG

The repeat is found in the 3′ untranslated region of the DMPK gene on chromosome 19.

Question 23

How does a mutation in an untranslated portion of DMPK affect myotonic dystrophy?

Answer 23

It produces an mRNA that remains in the nucleus and interacts with RNA-binding proteins, causing abnormal protein formation

This leads to pleiotropic features of the disease phenotype.

Question 24

What is a key feature of myotonic dystrophy type 2?

Answer 24

It is caused by a 4-bp (CCTG) expanded repeat in a gene on chromosome 3

Type 2 generally has a later age of onset and milder symptoms compared to type 1.

Question 25

What are the three broad categories of diseases caused by repeat expansions?

Answer 25

1. Neurological diseases 2. Phenotypically diverse diseases 3. Diseases like fragile X syndrome and myotonic dystrophy ## Footnote Each category varies in terms of repeat size, location, and phenotypic consequences.

Question 26

Define anticipation in genetic diseases.

Answer 26

Progressively earlier or more severe expression of a disease in more recent generations ## Footnote Anticipation is often linked to repeat expansions.

Question 27

What is fragile X syndrome characterized by?

Answer 27

Intellectual disability, distinctive facial appearance, hypermobile joints, and macroorchidism in males ## Footnote The syndrome is caused by a mutation in the FMR1 gene.

Question 28

What is the repeat sequence associated with fragile X syndrome?

Answer 28

CGG ## Footnote Affected individuals typically have 200 to 1000 or more repeats.

Question 29

What is the Sherman paradox?

Answer 29

The observation that mothers of transmitting males have a lower percentage of affected sons than daughters of these males ## Footnote This paradox is explained by the dynamics of repeat expansion in female transmission.

Question 30

What are normal transmitting males in fragile X syndrome?

Answer 30

Males who carry a premutation but do not show symptoms of fragile X syndrome ## Footnote They can pass the premutation to their offspring, leading to potential expansion.

Question 31

What happens to mRNA levels in individuals with FMR1 premutations?

Answer 31

They exhibit elevated mRNA expression, which accumulates in the nucleus and has toxic effects ## Footnote This can lead to neurological diseases and premature ovarian insufficiency.

Question 32

What is the inheritance pattern of myotonic dystrophy?

Answer 32

Autosomal dominant ## Footnote Both types can be inherited from either parent, but type 1 expansion to congenital form typically occurs through the mother.

Question 33

Fill in the blank: The expanded repeat in myotonic dystrophy type 1 leads to a _______ that remains in the nucleus.

Answer 33

toxic mRNA

Question 34

True or False: The degree of intellectual disability in fragile X syndrome is more severe in females than in males.

Answer 34

False ## Footnote The degree of intellectual disability tends to be milder and more variable in females.

Question 35

What are the phenotypic consequences of repeat expansions in the first category of genetic diseases?

Answer 35

Typically neurological diseases with clear symptoms such as motor control loss and dementia ## Footnote Examples include Huntington disease and spinocerebellar ataxias.

Question 36

What is the normal range of repeats for Huntington disease?

Answer 36

6 to 34 ## Footnote The disease-causing range is approximately 36 to 121 repeats.

Question 37

What is the estimated prevalence of FMR1 premutations in females?

Answer 37

About 1 in 200 females has an FRM1 premutation. ## Footnote This condition can lead to premature ovarian insufficiency.

Question 38

What is the estimated prevalence of FMR1 premutations in males?

Answer 38

About 1 in 600 males has a premutation. ## Footnote This is significantly less common than in females.

Question 39

What is the transcription status of the FMR1 gene in individuals with full mutations?

Answer 39

No FMR1 mRNA is present in their cells. ## Footnote This indicates a complete lack of transcription of the gene.

Question 40

What happens to the CGG repeat in individuals with a full mutation of FMR1?

Answer 40

The CGG repeat is heavily methylated. ## Footnote Methylation affects gene expression and is correlated with disorder severity.

Question 41

What is correlated with the severity of expression of fragile X syndrome?

Answer 41

The degree of methylation of the FMR1 gene. ## Footnote Higher methylation levels are associated with more severe symptoms.

Question 42

What percentage of individuals with fragile X syndrome do not have an expansion of the CGG repeat?

Answer 42

Less than 5%. ## Footnote These individuals may have loss-of-function mutations instead.

Question 43

What types of mutations can cause loss-of-function in the FMR1 gene?

Answer 43

* Nonsense mutations * Deletions ## Footnote These mutations result in a functional deficiency of the FMR1 protein.

Question 44

What is the role of the protein product of FMR1, FMRP?

Answer 44

FMRP binds to RNA and shuttles between the nucleus and cytoplasm. ## Footnote It plays a crucial role in mRNA transport and translation regulation.

Question 45

What is one of the main functions of FMRP in the cell?

Answer 45

Transporting mRNA from the nucleus to the cytoplasm. ## Footnote This function is essential for proper protein synthesis.

Question 46

What has the identification of the FMR1 gene helped improve in fragile X syndrome?

Answer 46

Diagnostic accuracy for the condition. ## Footnote Cytogenetic analysis often fails to identify fragile X heterozygotes.

Question 47

What does DNA diagnosis for fragile X syndrome involve?

Answer 47

Measurement of the length of the CGG repeat sequence and the degree of methylation of FMR1. ## Footnote This method is more reliable than cytogenetic analysis.