Genetic Diseases

Question 1

What is a molecular pathology ?

Answer 1

Why a genetic change (mutation) results in a clinical phenotype

Question 2

What are the types of mutations in genetic diseases?

Answer 2

Deletion, insertion, single base substitution

Question 3

What is a missense mutation?

Answer 3

Amino acid replaced with different amino acid

Question 4

What is a nonsense mutation? And what decay can it activate

Answer 4

Amino acid codon replaced with stop codon. Can activated nonsense mediated mRNA decay.

Question 5

What is a splice shift and what effect can it have?

Answer 5

When intron/exon splice sites are lost or created. Result in frameshift mutation

Question 6

What are the effects of different types of mutations?

Answer 6

• Loss of function
• Gain of function mutations
• Dominant negative mutations
• mutations that affect gene dosage

Question 7

What is a loss of function mutation? Give an example of a disease caused by a loss of function mutation.

Answer 7

Gene product has reduced or none of normal function. Any mutation that inactivates gene product will result in the same clinical symptoms. E.g Duchenne Muscular Dystrophy (DMD)

Question 8

What are the characteristics of Duchenne muscular dystrophy?

Answer 8

• Progressive muscular weakness
• Death in 3rd decade
• mostly males affected but occasionally females
• inherited- occurs in families (1 in 3500 male births)
• Treatment- none
• X-linked recessive

Question 9

What causes Duchenne muscular dystrophy?

Answer 9

No detectable dystrophin expression- lack of dystrophin protein.

Question 10

What is an indication someone has Duchenne muscular dystrophy?

Answer 10

Growers sign- patient that has to use their hands and arms to walk up body from a squatting position due to lack of hip and thigh muscle strength.

Question 11

What is a gain of function mutation? Give an example

Answer 11

Gene product acquires new abnormal function. Only the specific mutation that gives the product its new function will result in the clinical phenotype. E.g Huntington disease

Question 12

What are the characteristics of Huntington disease?

Answer 12

• Late onset, neurodegenerative, lethal disorder, dominant
• Strikes in midlife (30-50 years)
• Death of medium spiny neurons in striatum
• Motor, emotional and cognitive symptoms
• Death within 15-20 years

Question 13

What causes Huntington disease? How many alleles?

Answer 13

Mutation occurs as expansion of unstable CAG repeat within the coding gene sequence for the protein Huntington.
- 36- 100 CAG repeats
- mutated allele transcribed and translated to encode a polyglutamine tract in the protein- causes the protein to aggregate causing tract in neuronal cells death

Question 14

In Huntington disease what causes early onset?

Answer 14

Having more CAG repeats

Question 15

What is dominant negative mutations? Give an example

Answer 15

— Mutant gene product not only loses its own function but also prevents other gene products from functioning correctly.
Commons where mutation affects a multimeric protein encoded by more than 1 gene

Osteogenesis imperfecta

Question 16

What causes osteogenesis imperfecta?

Answer 16

Mutations in either COL1A1 or COL1A2 which encode for 2 alpa 1 chains and 1 alpha 2 chains, which exist as triple helix to make up type 1 collagen. Results in brittle bones;.

Question 17

In osteogenesis imperfecta there are a wide range of phenotypes that can be expressed. What are these and what causes them?

Answer 17

Mild phenotype- when the mutated alpha chain is excluded from type 1 collagen
Lethal phenotype- the mutated alpha chain is incorporated into type 1 collagen

Question 18

What is gene dosage effects? Give an example

Answer 18

Mutation varies level of gene product- effect depends on gene and cell type/
E.g Down syndrome - has an extra but normal chromosome 21 - lethal phenotype associated with 50% increase in dosage of chromosome 21.

Question 19

What is the definition of locus?

Answer 19

individual genes or DNA in our nuclear DNA have a chromosomal location that defines its position

Question 20

What is the definition for allele?

Answer 20

individual copy of a gene that is present at a locus on a single chromosome - humans are diploid- 2 alleles for each chromosomal locus, one inherited from mother and one from father

Question 21

What is a genotype?

Answer 21

Combination of alleles that a person possesses at a locus

Question 22

What does hemizygous mean and give an example?

Answer 22

genes with no allelic counterpart, such as XY chromosomes in males

Question 23

What are the 5 types of mendelian patterns?

Answer 23

autosomal dominant, autosomal recessive, x-linked dominant, x-linked recessive, y-linked

Question 24

what are features of an autosomal dominant disease?

Answer 24

manifests in both males and females, disease locus is in 1 autosome, both sexes are equally likely to transmit and there is a 50% chance of giving offspring the disease

Question 25

give the features of achondroplasia and what type of disease it is

Answer 25

heterozygous mutation in FGFR3 gene results in disproportionate small stature. individuals with AP who have healthy partner means children have a 50% chance of having AP. when both parents have AP, child has 25% chance of being healthy, 50% chance of AP and 25% chance of having homozygous AP which is lethal

Question 26

what type of disease is familial hypercholesterolemia and what does it cause

Answer 26

autosomal dominant. causes an elevation of serum cholesterol bound to LDL, deposits cholesterol in skin, arteries and tendons. has a heterozygous form which is less severe and a homozygous form which is more severe, presents earlier and as a higher range of cholesterol deposited

Question 27

what is an autosomal recessive disease and features

Answer 27

can happen in either sex, usually born to 2 carrier heterozygotes that have one normal and one mutant allele. mutant alleles may be different and result in compound heterozygote offspring if one of each mutant is inherited.

Question 28

what type of disease is cystic fibrosis and what are its features

Answer 28

autosomal recessive. mutant CFTR protein which regulates salt and liquid flow in cells. mutated means that respiratory system is damaged, causes buildup in pancreas that prevents insulin production and digestive enzymes reaching the intestines

Question 29

what is an x-linked recessive disease

Answer 29

usually only affects males, born to unaffected parents and inherits the mutation from the mother. if mutant is inherited from father, no infection risk but females will be a carrier. if inherited from mother, female has 1/2 chance of being a carrier, male has 1/2 chance of being affected

Question 30

what is an x-linked dominant disease

Answer 30

affects either male of female but usually more female, no father to son transmission. each child of an affected parent has 50% chance of infection. affected mothers have 50% chance of passing onto a son or daughter. if father is infected, e cannot transmit the X to his son, yet his daughters will inherit the X and be infected

Question 31

What is locus heterogeneity and examples

Answer 31

failure of a pathway involving many genes - defect in any of these genes can cause a clinical outcome, so the same recessive disorder may not have affected offspring. such as autosomal recessive deafness, usher syndrome, bardet beidle syndrome

Question 32

how can autosomal recessive deafness result in offspring being not deaf even if both parents are homozygous for the mutation?

Answer 32

the parents have different mutations in deaf genes as there are 2 different loci causing deafness called deaf1 and deaf2

Question 33

how can Bardet Biedl syndrome cause offspring with no symptoms even if both parents are homozygous

Answer 33

symptoms can be caused by mutations in any of at least 15 genes that regulate cilia function. mutations are at different loci

Question 34

what is penetrance and non-penetrance

Answer 34

penetrance = probability in a single gene disorder that the mutant allele will express the disease phenotype. dominant conditions have 100% penetrance
non penetrance = when variable expressibility is shown due to epigenetics, genes, environment altering phenotype expression