Gene environment interactions 18/10/22

Question 1

What is Retinitis pigmentosa and its symptoms?

Answer 1

Retinitis pigmentosa is a group of related eye disorders that cause progressive vision loss. These disorders affect the retina, which is the layer of light-sensitive tissue at the back of the eye, gradually deteriorate and this leads to vision loss.

The first sign of retinitis pigmentosa is usually a loss of night vision, later, the disease causes blind spots to develop in peripheral vision which can cause tunnel vision. In adulthood, many people with retinitis pigmentosa become legally blind.

Typically, RP is nonsyndromic which means the disorder occurs by itself.
Less commonly, RP is syndromic which means the disorder occurs as part of syndromes that affect other organs and tissues in the body. The most common form of syndromic RP is Usher syndrome.

Question 2

What kind of heterogeneity is RP?

Answer 2

It is locus heterogeneity.

Question 3

What inheritance is RP?

Answer 3

This disorder can be inherited by:

Autosomal dominant inheritance 15-25%
Autosomal recessive inheritance 5-20%
X linked inheritance 5-15% (in this case males mostly experience more severe symptoms)
Simplex 40-50% (this is when there is no inheritance known and most likely the disease occurred due to a de novo mutation)
Digenic small% (mechanism that occurs when the interaction of two genes is required for the expression of a phenotype)

Question 4

Is RP a loss or gain of function?

Answer 4

Recessive RP is usually associated with loss of rhodopsin function.
Dominant RP is usually associated with gain of function mutations.

Question 5

How common is RP?

Answer 5

Retinitis pigmentosa is one of the most common inherited diseases of the retina (retinopathies). It is estimated to affect 1 in 3,500 to 1 in 4,000 people in the United States and Europe.

Question 6

What genetics cause RP?

Answer 6

More than 80 mutations are known to cause nonsyndromic RP.

Mutations in the RHO gene (long arm of chromosome 3) are the most common cause of autosomal dominant retinitis pigmentosa.
Mutations in the USH2A are responsible for cases of autosomal recessive retinitis pigmentosa and can also cause ushers syndrome.
Mutations in the RPGR and RP2 genes account for most cases of X-linked retinitis pigmentosa.
Mutations in the peripherin/RDS and ROM1are responsible for digenic causes.

Question 7

What causes RP?

Answer 7

The genes of RP are associated with photoreceptors in the retina. Two types of photoreceptors - rods and cones.
Rods - low light vision
Cones - bright coloured light vision
Rods break down before cones explains first night vision impairment symptom.

RHO encodes rhodopsin. Rhodopsin is the light-absorbing molecule that initiates signal transduction in rod photoreceptor cells. The rhodopsin protein is bound to a molecule called 11-cis retinal, which is a form of vitamin A. When light hits this molecule, it activates rhodopsin and sets off a series of chemical reactions that create electrical signals. These signals are transmitted to the brain, where they are interpreted as vision. A few mutations cause rhodopsin to be constitutively activated instead of being activated in response to light. Studies suggest that altered versions of rhodopsin interfere with essential cell functions, causing rods to undergo apoptosis.

The USH2A gene provides instructions for making a protein called usherin. Usherin is an important component of basement membranes and is found in basement membranes in the inner ear and in the retina. Studies suggest that it is part of a protein complex that plays an important role in the development and maintenance of cells in the inner ear and retina and in the function of synapses. A single mutation causes the same issues like in RHO.

X -linked RP mainly affects males, causing night blindness in early childhood followed by progressive daytime vision loss. Most mutations in the RP2 gene lead to the production of an abnormally short version of the RP2 protein. A few mutations change single building blocks (amino acids) in the RP2 protein. These changes alter the structure and function of the protein, which probably disrupts the stability or maintenance of photoreceptor cells. A gradual loss of photoreceptors underlies the progressive vision loss characteristic of retinitis pigmentosa.

Question 8

What is Ushers syndrome?

Answer 8

Ushers’ syndrome combines retinitis pigmentosa with hearing impairment. In those with RP about 10% to 20% of persons have Usher syndrome.

At least 11 genes are known to cause Usher’s syndrome, which is split into 3 types based on clinical features. Interestingly depending on the type and position of the mutations within these genes they can also cause either retinitis pigmentosa without hearing loss or deafness without retinitis pigmentosa.

Question 9

What is Bardet-Biedl syndrome?

Answer 9

Bardet-Biedl syndrome combines retinitis pigmentosa with variably associated to obesity, cognitive impairment, polydactyly (extra fingers or toes), hypogenitalism, and renal disease. Syndromic retinitis pigmentosa is also associated with systemic metabolic and mitochondrial disorders.

In those with RP 5% of RP cases occur as part of the Bardet–Biedl syndrome, in which mental retardation and obesity are also observed.

Question 10

What can mitochondrial mutations do in RP?

Answer 10

Neuropathy, ataxia, and retinitis pigmentosa (NARP) is caused by mutations in MT-ATP6 which is involved in ATP production. Symptoms include muscle weakness, vision loss, and nerve signalling issues.

Question 11

How can gene replacement therapy help in people with RP?

Answer 11

In people with RP caused by the RPE65 mutation or LCA (Leber congenital amaurosis), an early onset version of RP also caused by RPE65 mutations. The gene therapy treatment gives patients a normal copy of the gene RPE65 with a surgical injection behind the retina. Adeno-associated viruses (AAVs) are the vector used to carry the DNA to the gene. AAVs are a type of parvovirus and can transduce nondividing cells. They have little pathogenic effect. This helps restore a patient’s vision.

Question 12

How can mitochondrial gene replacement therapy help in people with RP?

Answer 12

The egg cell contains the unhealthy mitochondria, and this is removed from the egg cell in IVF, a donor’s mitochondria is placed into the egg cell of the mother and then the egg cell is fertilised by the father’s sperm cell. This produces a child will normal and healthy mitochondria.

Question 13

What is Marfan syndrome and its symptoms?

Answer 13

Marfan syndrome is a disorder that affects the connective tissue in many parts of the body. Connective tissue provides strength and flexibility to all structures in the body. Marfan syndrome can affect many systems, often causing abnormalities in the heart, blood vessels, eyes, bones, and joints.

-Ectopic lentis
-Aortic aneurysm
-Aortic dissection
-Mitral valve prolapse
-Aortic problems lead to a shortness of breath, fatigue, and an irregular heartbeat.

Other symptoms are:
-Tall and slender
-Elongated fingers and toes (arachnodactyly)
-Crowded teeth
-Scoliosis or kyphosis
-Sunken chest or protruding chest

Marfan syndrome can be fatal early in life, however, with proper treatment, many affected individuals have normal lifespans.

Question 14

What heterogeneity is Marfan’s syndrome?

Answer 14

Allelic heterogeneity.

Question 15

Is Marfan’s syndrome a loss or gain of function?

Answer 15

This is a loss of function disorder.

Question 16

What inheritance is Marfan’s syndrome?

Answer 16

This condition is inherited in an autosomal dominant pattern and at least 25% of Marfan syndrome cases result from a new mutation in the FBN1 gene. These cases occur in people with no history of the disorder in their family.

Question 17

How common is Marfan’s syndrome?

Answer 17

The incidence of Marfan syndrome is approximately 1 in 5,000 worldwide.

Question 18

What genetics case Marfan’s syndrome?

Answer 18

Mutations in the FBN1 gene cause Marfan syndrome.

Question 19

What causes Marfan’s syndrome?

Answer 19

The FBN1 gene provides instructions for making a protein called fibrillin-1. Fibrillin-1 binds to other fibrillin-1 proteins and other molecules to form threadlike filaments called microfibrils. Microfibrils become part of the fibres that provide strength and flexibility to connective tissue. Additionally, microfibrils bind to molecules called growth factors and release them at various times to control the growth and repair of tissues and organs throughout the body. A mutation in the FBN1 gene can reduce the amount of functional fibrillin-1 that is available to form microfibrils, which leads to decreased microfibril formation. As a result, microfibrils cannot bind to growth factors, so excess growth factors TGF-β are available and elasticity in many tissues is decreased, leading to overgrowth and instability/inflexibility of tissues in Marfan syndrome.

Question 20

What is a de novo mutation?

Answer 20

An alteration in a gene that is present for the first time as a result of a mutation in a germ cell (egg or sperm) of one of the parents or soon after fertilisation.

Question 21

What somatic mosaicism?

Answer 21

A mutation in a single gene that can be somatic (i.e., in most body cells).

Question 22

What is gonadal mosaicism?

Answer 22

A mutation in a single gene that can be gonadal (i.e., confined solely to the gonads).

Question 23

What is penetrance?

Answer 23

Penetrance is the proportion of individuals carrying a particular variant of a gene that also express the symptoms of the disorder.

Question 24

What is BRCA1 and BRCA2?

Answer 24

BRCA1 and BRCA2 have been identified as major contributors to inherited breast cancer. They act as a tumour suppressor, controlling cell growth and cell death and are involved in DNA repair, particularly double stranded break repair and have possible roles in embryo development.

Question 25

What are some breast cancer risk factors?

Answer 25

• Obesity
• Smoking
• Alcohol consumption
• Menopause
• Child birth
• Oral contraception
• Radiation exposure
• Insufficient exercise
• Genetics

Question 26

What are common genetic variants that cause breast cancer?

Answer 26

BRCA1 and BRCA2 15%
CHEK2, ATM, and PALB2 2%
TP53 and PTEN 2%
Common variants 16%

Question 27

What are polygenic traits?

Answer 27

Polygenic traits/disorders are ones whose phenotype is influenced by more than one gene.

Question 28

What are complex traits?

Answer 28

Complex traits/disorders are believed to result from variation within multiple genes and their interaction with behavioural and environmental factors.

Question 29

What is a polygenetic risk score?

Answer 29

A polygenic risk score is an estimate of an individual’s genetic liability or relative risk of a trait or disease.
The score uses risk data for variants showing association to the trait/disease in GWAS to calculate a combined score for the relative risk of the individual dependant on which of these genetic variants they carry. Generally, doesn’t explain all the risk.

Question 30

What is Parkinson’s disease and its symptoms?

Answer 30

Parkinson disease is a progressive disorder of the nervous system. The disorder affects several regions of the brain, especially an area called the substantia nigra that controls balance and movement.

The first symptom of Parkinson disease are tremors of a limb. Tremors can also affect the arms, legs, feet, and face. Other symptoms include rigidity or stiffness of the limbs and torso, slow movement (bradykinesia) or an inability to move (akinesia), impaired balance and coordination (postural instability), cognition problems, psychiatric conditions such as depression and visual hallucinations, and an increased risk of developing dementia, which is a decline in intellectual functions including judgment and memory.

Generally, Parkinson disease that begins after age 50 is called late-onset disease. The condition is described as early-onset disease if signs and symptoms begin before age 50. Early-onset cases that begin before age 20 are sometimes referred to as juvenile-onset Parkinson disease.

Question 31

Is Parkingtons a loss or gain of function?

Answer 31

This is a loss of function disorder.

Question 32

What inheritance is Parkinson’s?

Answer 32

Most cases of Parkinson disease occur in people with no apparent family history of the disorder. These sporadic cases may not be inherited, or they may have an inheritance pattern that is unknown.

If the LRRK2 or SNCA gene is involved, the disorder is inherited in an autosomal dominant pattern.
If the PARK7, PINK1, or PRKN gene is involved, Parkinson disease is inherited in an autosomal recessive pattern.
Alterations in GBA and UCHL1 do not cause Parkinson disease but appear to modify the risk of developing the condition in some families.

Question 33

How common is Parkingtons?

Answer 33

It effects 2-3% of individuals aged 65 and over and is more common in men than women.
Incidence is high in Israel, possibly due to the high prevalence of the incompletely penetrant LRRK2 and GBA variants in Ashkenazi Jews. Prevalence is also high in Inuit, Alaska Native and Native American population, and individuals with high exposure to pesticides. Differences in prevalence between genders is lower in Japan.

Question 34

What genetics cause Parkingtons?

Answer 34

LRRK2, PARK7, PINK1, PRKN, or SNCA gene is involved in causing inherited Parkinsons disease. Only 5-10% of cases are heritable forms of Parkinson’s, with the rest are sporadic which the cause of isn’t always known.

Question 35

What causes Parkinson’s?

Answer 35

Many Parkinson disease symptoms occur when neurons in the substantia nigra die or become impaired. Normally, these cells produce dopamine, which transmits signals within the brain to produce smooth physical movements. When these dopamine-producing neurons are damaged or die, communication between the brain and muscles weakens. Eventually, the brain becomes unable to control muscle movement.

Some gene mutations appear to disturb the cell machinery that degrades unwanted proteins in dopamine-producing neurons. As a result, undegraded proteins accumulate, leading to the impairment or death of these cells.

Other mutations may affect the function of mitochondria, the energy-producing structures within cells. As a by-product of energy production, mitochondria make unstable molecules called free radicals that can damage cells. Cells normally counteract the effects of free radicals before they cause damage, but mutations can disrupt this process. As a result, free radicals may accumulate and impair or kill dopamine-producing neurons.

In most cases of Parkinson disease, protein deposits called Lewy bodies appear in dead or dying dopamine-producing neurons. (When Lewy bodies are not present, the condition is sometimes referred to as parkinsonism.) It is unclear whether Lewy bodies play a role in killing nerve cells or if they are part of the cells’ response to the disease.

Question 36

What is dementia and the difference between Alzheimer’s and Parkinson’s?

Answer 36

Dementia is the general term for Alzheimer disease.

Dementia - a general term for the impaired ability to remember, think, or make decisions that interferes with doing everyday activities.
Alzheimer - a condition where cognitive symptoms appear first and then physical ones.
Parkinson - a condition where physical symptoms appear first and then cognitive ones.

Other forms include:
- Vascular dementia.
- Dementia from Parkinson’s disease and similar disorders.
- Dementia with Lewy bodies.
- Frontotemporal dementia
- Mixed dementia

Question 37

How common is dimentia?

Answer 37

Around 50,000 people are estimated to be living with dementia in the UK.

Question 38

What is Alzheimer’s and its symptoms?

Answer 38

Alzheimer disease is a degenerative disease of the brain that causes gradual loss of memory, judgment, and ability to function.

Memory loss, lost in familiar settings, preparing meals, doing laundry, and performing other household chores can be challenging, difficultly to recognize people and name objects, personality and behavioural changes, trouble interacting in a socially appropriate manner, agitation, restlessness, withdrawal, and loss of language skills.

Affected individuals usually survive 8 to 10 years after the appearance of symptoms, but the course of the disease can range from 1 to 25 years. Survival is usually shorter in individuals diagnosed after age 80 than in those diagnosed at a younger age. Death usually results from pneumonia, malnutrition, or general body wasting.

Alzheimer disease can be classified as early-onset or late-onset.

Question 39

Is Alzheimer’s a loss or gain of function?

Answer 39

This is a gain of function disorder.

Question 40

What inheritance is Alzheimer’s?

Answer 40

Early-onset familial Alzheimer disease is inherited in an autosomal dominant pattern.

The inheritance pattern of late-onset Alzheimer disease is uncertain. People who inherit one copy of the APOE e4 allele have an increased chance of developing the disease, those who inherit two copies of the allele are at even greater risk. Not all people with Alzheimer disease have the e4 allele, and not all people who have the e4 allele will develop the disease.

Question 41

How common is Alzheimer’s?

Answer 41

Alzheimer disease (AD) is the most common form of dementia, approximately 2/3 of dementia cases. This disorder usually appears in people older than age 65. Alzheimer disease currently affects more than 5 million Americans.

Question 42

What genetics cause Alzheimer’s?

Answer 42

Early onset and inherited Alzheimer’s were found from mutations in the APP, PSEN1, or PSEN2 genes.
In late onset Alzheimer’s a gene called APOE was found, particularly e4 allele.

Question 43

What causes Alzheimer’s?

Answer 43

In early onset Alzheimer’s mutations can cause large amounts of a toxic protein fragment called amyloid beta peptide to be produced in the brain. This peptide can build up in the brain to form clumps called amyloid plaques, which are characteristic of Alzheimer disease. A build-up of toxic amyloid beta peptide and amyloid plaques may lead to the death of nerve cells and the progressive signs and symptoms of this disorder.

In late onset the disorder is probably related to variations in one or more genes in combination with lifestyle and environmental factors. The APOE gene provides instructions for making a protein called apolipoprotein E. This protein combines with lipids in the body to form molecules called lipoproteins. Lipoproteins are responsible for packaging cholesterol and other fats and carrying them through the bloodstream. Researchers have found that this allele is associated with an increased number of amyloid plaques in the brain tissue of affected people and neurofibrillary tangles made up of tau protein. A build-up of amyloid plaques may lead to the death of neurons and the progressive signs and symptoms of this disorder.

Question 44

Why are those who have downs syndrome more likely to develop Alzheimer’s syndrome?

Answer 44

People with down syndrome have an increased risk of developing Alzheimer disease. Down syndrome occurs when a person is born with an extra copy of chromosome 21 in each cell. As a result, people with Down syndrome have three copies of many genes in each cell, including the APP gene, instead of the usual two copies.

Although the connection between Down syndrome and Alzheimer disease is unclear, the production of excess amyloid beta peptide in cells may account for the increased risk. People with Down syndrome account for less than 1 percent of all cases of Alzheimer disease but around half of people with down’s syndrome develop Alzheimer’s in their 50’s or 60’s. This type of Alzheimer disease is not inherited.

Question 45

What is X-inactivation?

Answer 45

X-chromosome inactivation is the transcriptional silencing of one X chromosome in female mammalian cells that equalizes dosage of gene products from the X chromosome between XX females and XY males. The inactivated X chromosome then condenses into a compact structure called a Barr body, and it is stably maintained in a silent state. It is silenced by being highly methylated so no transcription can occur. Therefore, from a female stem cell embryo only one X chromosome is ever active.

Question 46

What is the sympathetic-adrenomedullary (SAM) system?

Answer 46

The SAM system is best known for its role in responding to dangerous or stressful situations. The involves the hypothalamus and the adrenal medullary. This causes a faster heartbeat; the liver breaks down some of the stored glycogen into extra glucose, which is released into the blood, the arterioles change which leads to the digestive system constricting and those leading to the muscles dilate, bronchioles may widen so more air can enter/leave the lungs with each breath.

Question 47

What is the Hypothalamic-Pituitary-Adrenocortical (HPA) axis?

Answer 47

The HPA axis a term used to represent the interaction between the hypothalamus, pituitary gland, and adrenal glands, it plays an important role the body’s response to stress. The pathway of the axis results in the production of cortisol, and controls mechanisms such as the metabolism, immune system, homeostasis, and alertness.

Question 48

How does our environment and genes interact to cause disorders?

Answer 48

Gene mutations and environmental risk factors, pathways such as the SAM and HPA systems can also play a role. For example, chronic stress can cause depression, anxiety, cardiovascular disease, diabetes, and sleep disturbance.

Question 49

What is expressivity?

Answer 49

The degree to which a particular genotype expresses its phenotype.