PBL 3- Parkinsons/Huntingtons Flashcards
What are tandom repeats?
What are the different types?
What happens when you have too many?
What kind of symtpoms do you get?
- The human genome has many repeated DNA sequences of unknown or NO function
- They can be of any length
- A dinucleotide repeat is CGCGCGCG
- An excessive amount of repeats within a gene can disrupt the protein encoded by the gene
- This can lead to a SINGLE gene disorder
- Trinucleotide repeats “triplet” repeats can cause various human genetic disease
- Symptoms can vary greatly depending on which gene is disrupted
If different genes ultimately affect the same system then a mutation in any of these genes alone can lead to a clinically similar disease
What is Fragile X syndrome: What are the main features? What type of mutation causes it? What gene does it effect? What is the usual function of that gene? How do different amounts of repeats present?
Fragile X syndrome:
- Moderate to severe mental retardation - Macroorchidism (large testicles) - Distinct facial features- long face, large ears, prominent jaw
Large number of repeats =
> 200 CGC repeats in the fragile mental retardation 1 gene (FMR1)
- Encodes an RNA binding protein believed to be involved in transation - Large number of repeats leads to a loss of function of the FRMI gene
Shorter expanded CGC repeats (55-200)
- Termed premutations - Can give rise to Fragile X mutations in subsequent generations by expansion of the repeats - Cause a GAIN of function Protein levels are not much affected but the longer mRNA appears to cause nuclear damage leading to degeneration
What is Ataxia?
What is some genetic causes?
What are the types?
Ataxias
means
- Incoordination and unsteadiness due to the brains failure to regulate posture and limb movements appropriately - Often due to diseases affecting the cerebellym - Can have early or late onset (before or after 20-25)
Early onset forms:
- Usually autosomal recessive - EG = Friedrichs ataxia, usually involving triplet repeat mutations of the frataxin gene
Late onset: EG spinocerebellar ataxia
- Usually autosomal dominant
- All common forms SCA1 are due to triplet repeats
- Gait and balance impairments
- Other symptoms can include peripheral neuropahty, dementia, ophthalmaplegia
- Degeneration of the cerebellum and afferent/efferent connections in the brainstem and spinal cord
- SCA1= CAG triplet repeats in ATAXIN 1 function unknown but appears to be involved in cerebellar development
SCA6- most commonly due to CAG triplet repeats in a calcium channel gene CACN11A (single point mutation causes familial hemiplegic migraine)
What is Kennedy spinal and bulbar muscular atrophy?
What kind of mutation causes it?
- Triplet repeats in an androgen receptor
- Single point mutation in the same place causes very different disease- adrogen insensitivity syndrome- where chromosomal males can a female phenotype
- Myotonic dystrophy: MD1- dystrophia myotonica- protein kinase gene
MD2- zinc finger protein 9 gene
Generally, what is Huntingtons disease?
Fatal, adult onset neurodegenerative disease with movement chorea and cognitive symptoms
What genetic mutation causes it?
ie - what nucleotide pattern?
what does it code for? and what gene does it effect?
- Multiple repeats of the trinucleotide CAG In the coding region of the HTT gene
- Gene: IT15 gene encoding the huntingtin protein
- CAG encodes the amino acid glutamine (symbol Q)
- This causes multiple Q repeats in huntingin (also called polyglutamine or polyQ disease)
What inheritance pattern does Huntingtons follow?
when is it inherited in a more unstable fashion?
Autosomal Dominant
which is more unstable when inherited by the father
how many alleles need to be abnormal to inherit Huntingtons disease?
One
Does the Huntingtin protein end up with a loss or gain of function in HD?
What would happen if it was the other?
- Loss of function mutation in the HD gene causes fetal death not Huntingtons disease
- Expansion of CAG repeats causes a GAIN of function mutation
What is Anticipation?
Why does it occur?
How does it effect people clinically?
- Repeat sequences usually inherited in a stable fashion but can become unstable with increased repeats in offspring
- Expansion is probably due to slippage of DNA polymerases during DNA synthesis○ The enzyme “loses track” of where it is in the region of the repeats and incorporates more repeats
- Slippage in DNA replication in succeeding generations can cause increased disruption of the gene
This increases symptom severity and typically results in earlier onset of disease in children in comparison to their parents
How are trinucleotide repeats trasmitted?
ie in what stage of life?
does it have a bias?
- Repeat expansion occurs during gametogenesis, can also occur during spermatogenesis
- Repeat expansion shows a sex bias
- Occurs in three forms
○ Normal : number of repeats in stable and no change during gametogenesis
○ Pre-mutaiton: partially expanded = no symptoms however unstable during gametogenesis
Full mutation: symptoms
Why is the number of repeats important?
Do normal people have repeats?
How many repeats is needed to transmit or develop disease?
- Everyone has a few multiple CAG repeats in the huntingtin gene however the number is important for disease penetrance
- The more repeats the more abnormal the protein product, the more severe the symptoms and the earlier the age of onset.
- Has a dose effect
- 28 or less = normal range
- 29-34 = wont get HD but next generation is at risk
- 35-39 = Some will get HD but not all. Next generation at risk
More than 40 = Will get HD
When is the normal onset for Huntington’s?
when would you get it earlier?
- Usually in your 30s to 40s however the range can be from 2-82 years of age
- The onset usually gets younger with each generation (anticipation) and also there is earlier detection
- Over 60 repeats of CAG is associated with onset before age 20
- Usually more repeats = more severe disease however if your number of repeats is under 60 then it is highly variable
○ Likely to reflect modifying effects of other genetic and/or environmental factors
Is Parkinsons homogenous or heterogenous?
Whats the difference between monogenic forms and multifactorial forms of PD?
- Complex heterogenous genetic disease
- Distinct Parkinson’s disease subtypes with distinct genetic aetiologies, pathologies and symptoms
- Deficit of the NT-dopamine
No clear inheritance pattern
- Monogenic forms of PD caused by a mutation in a single gene ○ Mutations in several different genes can each individually give rise to Parkinsons disease ie each such mutation is sufficient but not necessary for development of parkinson's disease
Multifactorial forms of
Parkinson’s Disease- reflecting multiple genetic and or environmental factors and their interactions.
What causes monogenic forms of parkinsons disease?
What are some gene examples?
- Caused by a mutation in a single gene
- A-synuclein, Nurr1, Parkin- can each individually give rise to parkinson’s
- Various genetic loci (PARK 3, PARK 20 ) are linked to parkinson’s disease but the specific genes at these chromosomal locations that are causing the effects of the disease have not been identified.
SNCA, LRRK2, PINK1 have also been implicated in sporadic PD
PARKIN gene What chromosome and loci? what kind of parkinsons is it associated with? how common? when is the onset and progression? what does Parkin usually do? what does a mutation result in?
Parkin ( Chromosome 6, PARK 2)
- Implicated in autosomal recessive juvenile parkinsonism
- Rare
- Onset <40 years
- Slow course over decades
- Loss of nigral dopaminergic neurons but usually NO Lewy bodies or Lewy Neurties
- Over 1000 single nucleotide polymorphisms so far identified in the parkin gene
○ Some are harmless
○ Some may causes PD when homozygous - Parkin is an E3 ubiquitin ligase- it attaches short ubiquitin peptide chains to proteins to tag them for degradation through the proteasome pathway
- Parkin is involved in degradation of at least one form of synuclein and of at least one other neuronal protein that binds to a-synuclein
Mutations in parkin are likely to affect degradation of a- synuclein
A-Synuclein
What chromosome what loci? What kind of inheritance pattern? What kind of progression ? where is the mutation site?
(Chromosome 4, PARK 1/4)
- Autosomal dominant mutations in a-synuclein found in rare familial early onset forms of PD
- Rapid progresion and cognitive impairment
- Several different mutation sites in the a-synuclein gene
Mutation causes aggregation of the a-synuclein protein in lewy bodies
