Lecture 17

Question 1

From which parent is mitochondria inherited?

Answer 1

Mom

Question 2

What is heteroplasmy?

Answer 2

Mitochondrial DNA segregates passively when a cell divides, which leads to unequal distribution of mutant and non-mutant mitochondrial DNA, which is heteroplasmy in mitochondrial disorder, so each ovum has different amount of mutated mitochondrial gene in it, causing different expression in each offspring.

Question 3

How can variable expression of the mitochondrial disorder be explained?

Answer 3

Heteroplasmy

Question 4

What is MELAS?

Answer 4

Associated phenotype for mitochondrial disorder
Mitochondrial encephalomyopathy,
Lactic Acidosis
Stroke-like episodes

Question 5

What is Leber hereditary optic neuropathy?

Answer 5

Manifest as progressive blindness around 20-30 yrs.

Question 6

Does mitochondrial mutation generally affect multiple organ systems?

Answer 6

YES

Question 7

What is MERRF (in terms of mt disorder)

Answer 7

Myoclonic epilepsy with ragged red muscle fiber

Question 8

1 example of digenic disorder

Answer 8

Retinitis pigmentosa

Question 9

Example of imprinting(2)

Answer 9

1. Prader Willi syndrome

2. Angelman syndrome

Question 10

3 examples of triplet repeat disorder with anticipation(3)

Answer 10

1. Huntington disease
2. Myotonic dystrophy
3. Fragile X syndrome (X-linked)

Question 11

Mode of transmission of myotonic dystrophy

Answer 11

Autosomal dominant

Question 12

What digenic disorder?

Answer 12

Mutations in two genes are additive and necessary to produce disorder (heterozygote for gene A and geneB=AaBb) which is not seen without the other!

Question 13

Manifestation of Retinitis pigmentosa

Answer 13

progressive visual impairment caused by mutation in ROM1 and peripherin genes

Question 14

What is normal imprinting effect on chromosome 15?

Answer 14

SNRPN gene is silenced by methylation on maternal ch15, while is active on paternal ch15.
Then, UBE3A gene is active on maternal ch15, while it is silenced on paternal ch15.

Question 15

What are genes of chromosome 15 that are involved with imprinting?

Answer 15

SNRPN and UBE3A

Question 16

What causes Prader Willi syndrome? (2)

Answer 16

caused by microdeletion of paternal chromosome 15 (SNRPN) (70% of case)
or maternal uniparental disomy of chromosome 15 caused by nondisjunction.

Question 17

Manifestation of Prader Willi syndrome(4)

Answer 17

1. Obesity
2. Mental and developmental delay
3. Underdeveloped genitalia
4. Hypotonic in infancy

Question 18

Mechanism of Prader Willi syndrome

Answer 18

Usually paternal chromosome produces SNRPN, however, microdeletion on paternal chromosome 15 disables SNRPN gene leading to no active copy of SNRPN. UBE3A gene on maternal gene is still active.

Question 19

How is Prader Willi Syndrome caused by uniparental disomy?

Answer 19

In this condition, there are two copies of maternal chromosome 15 without any copy of paternal chromosome. As a result both copies of maternal chromosome 15 are methylated (silenced), leading to two active copies of UBE3A and no active copies of SNRPN gene.

Question 20

What lab technique can be used to differentiate Prader Willi syndrome caused by uniparental disomy and microdeletion?(2)

Answer 20

Use methylation analysis aiming for SNRPN. For uniparental disomy, there will be two methylated copies of ch 15, while for microdeletion there will be single methylated copies for maternal chromosome.

Also, polymorphic marker analysis (target trisomy)

Question 21

Relationship between uniparental disomy and trisomy rescue

Answer 21

Due nondisjunction, zygote could have trisomy. When there are two copies of paternal chromosome with 1 copy of maternal chromosome, maternal chromosome is lost, resulting in daughter cell with paternal uniparental disomy (a phenomenon of trisomy rescue). It is called angelman syndrome

Also if there are two maternal chromosomes with one paternal chromosome, paternal chromosome is lost as trisomy rescue, resulting into a daughter cell with maternal uniparental disomy. (Prader-Willi syndrome)

Question 22

When is methylation analysis useful for uniparental disomy disorder?

Answer 22

Is it most useful when the children are very young and have not developed classical phenotypes of the disorder yet.

Question 23

How is Angelmen syndrome caused?(2)

Answer 23

• deletion of maternal chromosome 15q11-13, which leads to absence of active UBE3A gene
• Uniparental disomy of paternal chromosome 15 which leads to two copies of active SNRPN and absence of UBE3A gene.

Question 24

Manifestation of angelman syndrome(4)

Answer 24

1. Inappropriate laughter
2. Severe intellectual disability
3. Seizures
4. Puppet like posture of limbs

Question 25

4 classes of triplet repeat disorders

Answer 25

1. At the promoter region - CGG repeat (Fragile X syndrome)
2. In an intron - GAA repeat - resulting in formation of heterochromatin (Friedrich ataxia)
3. In the coding region of the gene - CAG repeat - resulting in polyglutamine expansion in protein (Huntington disease)
4. At the 3’end of the gene - CTG repeat- Myotonic dystrophy

Question 26

Example of disease that has triplet repeat disorder on promotor region

Answer 26

Fragile X syndrome

Question 27

Example of disease that has triplet repeat disorder on intron region

Answer 27

Friedrich ataxia

Question 28

Example of disease that has triplet repeat disorder on coding region

Answer 28

Huntington disease

Question 29

Example of disease that has triplet repeat disorder on 3’end (3’UTR) region

Answer 29

Myotonic dystrophy

Question 30

What is the phenomenon anticipation?

Answer 30

Individuals in the recent generation of a pedigree develop disease at an earlier age and with greater severity, due to mutation of higher number of repeat.

Question 31

Explain relationship between triple repeat expansion and anticipation.

Answer 31

More and larger the repeat, harder for polymerase to repair it, making it stutter, thus leading to greater number of repeats, leading to higher severity for later generation, which is anticipation

Question 32

3 example of disease that shows anticipation

Answer 32

1. Huntington disease (CAT repeat)
2. Myotonic dystrophy (expansion of repeat in mother)
3. Fragile X syndrome (repeat expansion in mother)

Question 33

Fragile X syndrome repeat sequence

Answer 33

CGG repeat

Question 34

What is mechanism of fragile X syndrome

Answer 34

CGG triplet repeat is present at 5’end of FMR1 gene, reuslting in increased methylation of this region and silencing of FMR1 gene.

Question 35

Manifestation of fragile X syndrome

Answer 35

intellectual disability, learning difficulties prominent ears, elongated face, enlarged testis