Lecture 17 Flashcards
From which parent is mitochondria inherited?
Mom
What is heteroplasmy?
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.
How can variable expression of the mitochondrial disorder be explained?
Heteroplasmy
What is MELAS?
Associated phenotype for mitochondrial disorder
Mitochondrial encephalomyopathy,
Lactic Acidosis
Stroke-like episodes
What is Leber hereditary optic neuropathy?
Manifest as progressive blindness around 20-30 yrs.
Does mitochondrial mutation generally affect multiple organ systems?
YES
What is MERRF (in terms of mt disorder)
Myoclonic epilepsy with ragged red muscle fiber
1 example of digenic disorder
Retinitis pigmentosa
Example of imprinting(2)
- Prader Willi syndrome
2. Angelman syndrome
3 examples of triplet repeat disorder with anticipation(3)
- Huntington disease
- Myotonic dystrophy
- Fragile X syndrome (X-linked)
Mode of transmission of myotonic dystrophy
Autosomal dominant
What digenic disorder?
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!
Manifestation of Retinitis pigmentosa
progressive visual impairment caused by mutation in ROM1 and peripherin genes
What is normal imprinting effect on chromosome 15?
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.
What are genes of chromosome 15 that are involved with imprinting?
SNRPN and UBE3A
What causes Prader Willi syndrome? (2)
caused by microdeletion of paternal chromosome 15 (SNRPN) (70% of case)
or maternal uniparental disomy of chromosome 15 caused by nondisjunction.
Manifestation of Prader Willi syndrome(4)
- Obesity
- Mental and developmental delay
- Underdeveloped genitalia
- Hypotonic in infancy
Mechanism of Prader Willi syndrome
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.
How is Prader Willi Syndrome caused by uniparental disomy?
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.
What lab technique can be used to differentiate Prader Willi syndrome caused by uniparental disomy and microdeletion?(2)
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)
Relationship between uniparental disomy and trisomy rescue
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)
When is methylation analysis useful for uniparental disomy disorder?
Is it most useful when the children are very young and have not developed classical phenotypes of the disorder yet.
How is Angelmen syndrome caused?(2)
- 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.
Manifestation of angelman syndrome(4)
- Inappropriate laughter
- Severe intellectual disability
- Seizures
- Puppet like posture of limbs
4 classes of triplet repeat disorders
- At the promoter region - CGG repeat (Fragile X syndrome)
- In an intron - GAA repeat - resulting in formation of heterochromatin (Friedrich ataxia)
- In the coding region of the gene - CAG repeat - resulting in polyglutamine expansion in protein (Huntington disease)
- At the 3’end of the gene - CTG repeat- Myotonic dystrophy
Example of disease that has triplet repeat disorder on promotor region
Fragile X syndrome
Example of disease that has triplet repeat disorder on intron region
Friedrich ataxia
Example of disease that has triplet repeat disorder on coding region
Huntington disease
Example of disease that has triplet repeat disorder on 3’end (3’UTR) region
Myotonic dystrophy
What is the phenomenon anticipation?
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.
Explain relationship between triple repeat expansion and anticipation.
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
3 example of disease that shows anticipation
- Huntington disease (CAT repeat)
- Myotonic dystrophy (expansion of repeat in mother)
- Fragile X syndrome (repeat expansion in mother)
Fragile X syndrome repeat sequence
CGG repeat
What is mechanism of fragile X syndrome
CGG triplet repeat is present at 5’end of FMR1 gene, reuslting in increased methylation of this region and silencing of FMR1 gene.
Manifestation of fragile X syndrome
intellectual disability, learning difficulties prominent ears, elongated face, enlarged testis
