Intro to genetics eye disease - week 3 Flashcards
List the 6 general patterns of Mendelian inheritance.
- Autosomal recessive
- Autosomal dominant
- x-linked recessive
- x-linked dominant
- codominant
- mitochondrial
Define Monogenic trait
A characteristic produced by a single gene or allele
Define Complex trait
A trait that does NOT follow Mendelian Inheritance patterns, is likely derived from multiple genes, and exhibits a large variety of phenotypes
How can glaucoma be inherited? (in terms of inheritance pattern)
Glaucoma can be inherited as a mendelian autosomal-dominant or recessive trait, OR as a complex multifactorial trait.
Explain the different frequencies and severities for monogenic and complex traits using glaucoma as an example
Mendelian inheritance i.e. monogenic traits (e.g. mutation in MYOC) will have the rarest frequency but the largest effect size
Complex traits are inherited through ‘modifiers’, which contribute to the disease (e.g. COL1SAT for glaucoma)
As an adult, what is the frequency and severity of the mutations in genes that modify SNPs? Give an example of one such gene
Common with low severity e.g. TMCO1
In the context of glaucoma, what traits are influenced by genes mutations that modify SNPs?
traits like IOP, corneal thickness that increase disease risk
Do genes mutations that modify SNPs always result in a disease?
No. e.g. High IOP doesn’t mean you have glaucoma. It just increases the risk
What proportion of STRAB patients have a family history of the condition?
~30%
Incidence of STRAB in general population
3%
What is the role of the genes associated with STRAB?
role in normal development of and/or connectivity of cranial motorneurons
Describe Congenital Nystagmus
Is an eye movement problem where the eye movement centres have lost control, and you get a ‘lateral jerk’
How many loci are associated with very high myopia? [must know]
18 loci
- 9 autosomal dominant (AD)
- 1 autosomal recessive (AR)
- 2 x-linked recessive (XL)
- 6 other loci
Which is the key gene that regulates lens development?
Pax6
Which gene leads to the development of lens crystallins?
CRY
- cry = “cry”stallin (Cry Stalin)
What gene that controls gap junctions can cause a congenital cataract when mutated?
Cx43
Where are aquaporins found in the eye? [name 3]
ciliary epithelium, corneal epithelium, conjunctival epithelium
What mutations can cause congenital cataract? [4]
Mutations of genes that control:
- lens development (Pax6)
- lens crystallins (CRY)
- gap junctions (Cx43)
- aquaporins
Why are gap junctions important for optical clarity?
Important for communication between fibres and between lesn capsule and it’s external environment. Therefore important for ionic transport which is important to maintain clarity
Define coloboma
Failure of fissure to close/incomplete closure
Define aniridia
Absence of the iris
Name 2 gene mutations that are associated with intraocular coloboma and aniridia
Pax6 gene mutation at 11p1
WT1 mutation
Name 3 genes assoc. with anopthalmia/microphthalmia
- Pax6
- OTX2
- NDP
Vaguely describe optic nerve hypoplasia in 4 words
Loss of O.N tissue
List the risk factors of Optic nerve hypoplasia (ONH):
- preterm birth
- alcohol
- quinine (for Malaria)
- phenytoin (for seizures + cardiac problems)
- Maternal diabetes
- Congenital Cytomegalocirus (CMV) infection
- LSD consumption
Vaguely describe the roles of transcription factors assoc. with ONH
Any transcription factors that are critical to the development of the eye and nuerogenesis
What is the role of the enzyme RPE65
RPE65 is essential for the recycling of the chromophore
What types of gene abnormalities can lead to retinal degeneration?
Abnormality in any gene that drives what photoreceptors do can lead to retinal degeneration
Name an example of retinal degeneration
Retinitis Pigmentosa
Briefly describe what happens in Retinitis Pigmentosa when the photoreceptors die off
When photoreceptors die off, the RPE can also die off – leading to clumping of pigmentation in the retina
This pigmentation is known as ‘bony spicule’
List the causes of Retinitis Pigmentosa (RP)? [7]
Mutations in proteins involved in:
- Phototransduction cascade
- Vitamin A metabolism
- Signalling, cell-cell interaction or synaptic interaction
- Trafficking of intracellular proteins
- Maintenance of cilia
- pH regulation (choriocapillaris)
- Phagocytosis
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How long does the recycling process of retinol/retinal take in dark adaptation?
Around 30 minutes
What condition do mutations in RPE65 lead to?
Leber’s Congenital Amaurosis (LCA)
How many different gene mutations can cause LCA?
mutations in more than 12 genes
How can we assess retinal function In Retinitis Pigmentosis subjectively and objectively?
Subjective:
- V.A, Contrast Sensitivity, Flicker Sensitivity, Dark Adaptation, Visual Fields
Objective:
- pupil responses, electrophysiology
Explain how the electrodes work in EOG.
Put electrodes on the temples and one electrode in the middle. As your eye is moved from side to side, the electron current will change direction which will be picked up by the electrodes –> this current/change is driven by potassium through the RPE
In which scenario does the RPE work harder: light or dark?
Dark. RPE works hard for recycling
What is the Arden Ratio?
is the ratio of the light peak to dark, and is used to determine the normalcy of the results in EOG
What values for Arden ratio are normal or abnormal? [own research]
Greater than 1.80 is normal
1.65 to 1.80 is subnormal
less than 1.65 is significantly subnormal
What is the typical Arden ratio?
Normally greater 2.0
Which type of retinal cell currents sum up, and which cancel?
Radial retinal cell currents sum up
Lateral currents cancel
What are the 2 pathways that light induced extracellular current divides into?
- Internal (local) current
2. External (remote) current
In ERG, which wave tells us about the muller cells?
The c wave
In ERG, which wave is associated with off bipolar cells
The d wave
In ERG, which wave is assoc. with on bipolar cells
The b wave
In ERG, which wave is assoc. with photoreceptors and reduction in dark current?
The a wave
Which retinal pathway do Amacrine cells belong to?
The Lateral pathway
How does the lateral pathway interact with the through pathway?
Lateral pathway modifies the response of the through pathway. e.g. it’s involved in inhibition etc
Which neurotransmitter is inhibitory GABA or GLUTA?
GABA
Which neurotransmitter is excitatory GABA or GLUTA?
GLUTA
Are amacrine cells glutaergic or gabaergic?
GABAergic
How does the brightness of the test flash affect the amplitude of the ERG? How would describe this phenomenon
makes it bigger. This is a Dose response function
What happens to the b-wave when you block glutamate?
It disappears
Where do mutations occur to cause Lebers hereditary optic nerve atrophy?
mutations in mitochondrial dna
