Week 9 - Genetics in opthalmology Flashcards
How does genetic risk and dietary protection affect AMD?
• Several little variants in DNA shown to affect each persons individual risk if developing AMD
• These inherited risks can be minimised by controlling other risk factors, (diet, exercise, weight, smoking)
Which compliment gene is a risk factor for AMD?
• Complement factor H
- Increases AMD risk factor by 7.4
• Also causes cases of kidney disease
- People with this mutation can see multiple drusen and increase risk of loss of central vision of 10%
What does the activation of the complement CFH result in?
• Inflammation to fight off infection - brings phagocytes
• A molecular battering ram that can punch holes in walls of cells/bacteria to destroy them
Whats the GOOD news (advice) about CFH related to AMD?
• If ones follows the diet, they can reduce risks by 50% over 7 years.
• Smokers develop AMD ten years earlier than they would have done not smoking
• Exercising 3 days a week cuts risk of late-stage AMD by 40%
What are some conditions that are the result of mutation?
• Sickle cell Haemoglobinopathy: Acid substitution
• Stickler syndrome: “stop” codon and protein truncation
• Rieger syndrome: frame shift
• Myotonic dystrophy: Triplet expansion
What is Gain of function and Haploinsufficiency of mutations?
• Gain of function : Protein works at wrong time, place or out if control.
• Haploinsufficiency: Gene product of both alleles is required, when amount of gene product is reduced by 50% by loss if function of the gene
What is Loss of function and Dominant negative mutations?
• Loss of function : loss of protein/enzyme activity
• Dominant negative mutation : Mutant gene loses function and stops new protein from working too
When are the mutations noticed?
• May not be noticed at birth:
- delayed onset e.g chorideraemia
- slow accumulation of damage e.g. corneal dystrophy
• Rare a genetic disorder may look worse at birth but less severe later on
What is autosomal recessive?
• If one copy of gene, the abnormality doesn’t affect child. Trouble only arrives when two copies are present.
- Stargardts disease
- Jalili syndrome
What is X-linked recessive?
• Only affected X chromosome
- Usually shows up on male
- Can also express with females, if disordered X chromosome with x chromosome inactivation
• Example : Choroidermia
What is Autosomal dominant?
Autosomal Dominant means that a normal gene from one parent is over-ruled by the abnormality of the gene inherited from the other parent.
What are examples of patterns of inheritance?
• Autosomal Recessive e.g. Stargardt’s disease (maculopathy); Jalili syndrome
• Autosomal Dominant e.g. Marfan syndrome
• X-linked recessive: normal copy of the gene protects females e.g. Red-green colour blindness; Choroideraemia.
Maternal pattern of inheritance?
• Mitochondria contain loop of their own DNA
• Egg provides all 100,000 mitochondria in zygote
- So diseases caused by mutations in the mitochondria are passed from mother to offspring
What are some diseases caused by Maternal mutations?
• Lebers hereditary optic neuropathy
• Maternally inherited diabetes + deafness
• Neuropathy, ataxia and retinitis pigmentosa
• Chronic progressive external opthalmoplegia
What is a Genotype and a phenotype?
• The genotype is the specific alteration of the DNA, affecting one or another part of a gene;
• The phenotype is the effect this has upon the organism.
What foes a mutation of gene BIG-H cause?
• Adult corneal dystrophy, specifically;
• Granular : Amorphous deposit, stains and masson trichrome
• Avellino
• Lattice : Abnormal folding of BIGH protein causes amlyoid deposition
Can diseases vary between family?
• Yes! There are variations with diseases, etc StarGardts disease
• Best’s disease : only 50% look abnormal
• This is called Variable Expressivity
What causes Jalili syndrome?
• Mutation in gene for putative metal transport
• Expressed in developing teeth, causes hypo-maturation of enamel
• Also expressed in inner segments of photoreceptors
What causes FEVR syndrome?
• Due to defective signalling to endothelial cells
• Extracellular signals ineffective at signalling to intracellular, results in insufficient expression of the gene in cell
What is the biology of retinoblastoma?
• Product of RB1 gene is phosphoprotein, pRB1
• Interacts with many proteins in regulation if cell cycle, differentiation and control of genomic stability
• DNA tumour viruses that induce cancer - do so by binding to pRB1
• This mutation increases retinoblastoma risk by 40,000x and sarcoma by 500x
How has
