Basic Genetic Pathology

Question 1

____ of spontaneous abortions/miscarriages have a chromosomal abnormality

Answer 1

50%

Question 2

__ of those under age 25 develop a disease with a significant genetic component

Answer 2

5%

Question 3

Estimated that lifetime frequency is ___/1000

Answer 3

670

Question 4

3 types of point mutations:

Answer 4

1. substitution
2. insertion
3. deletions

all involving changes at one (or very few) nucleotides

Question 5

Substitutions can be:

Answer 5

Transitions
Transversions

Question 6

-interchanges of purines (A, G) or of pyrimidines (C, T)
- involve bases of similar shape (both one ring or both two ring)

Answer 6

Transitions

Question 7

-interchanges of purine for pyrimidine bases
- involve an exchange of one-ring and two-ring structures

Answer 7

Transversions

Question 8

Insertions or deletions of single nucleotides can lead to _________ mutations – all of the triplets are off by one. What are these often called?

Answer 8

frameshift
“frame-shifting indels”

Question 8

What does a frame-shift mutation often result in?

Answer 8

Often results in total loss of function of the protein:

Question 9

“O” blood type results from a ________ mutation and loss of function of the red blood cell antigen

Answer 9

frameshift

Question 10

non-frameshifting “indels”

Answer 10

▪ If a multiple of three nucleotides are inserted or deleted, then the reading frame is preserved

Example – most common cystic fibrosis mutation

Question 11

One nucleotide deletion –
frameshift would result in

Answer 11

Protein is no longer functional

Question 12

Three nucleotide deletion –
non-frameshift would result in? This is the most common mutation in _________

Answer 12

loss of an amino acid
Most common mutation in cystic fibrosis

Question 13

point mutation = little or no change in function

Answer 13

Silent or conservative missense

Question 14

Point mutation: a significant change in function. What is an example?

Answer 14

nonconservative missense
Example – sickle cell anemia

Question 15

If the nucleotide triplet being changed becomes a stop codon, then premature ending of translation. What would this result in?

Answer 15

non-sense mutation
truncated (shortened) protein
Example – some types of thalassemia

Question 16

what is an example of nonsense?

Answer 16

beta-thalassemia

Question 17

explain how due to a mutation, some people can’t be infected by the HIV virus

Answer 17

HIV uses a chemokine receptor, CCR5, to
enter cells; a deletion in the CCR5 gene
thus protecting from HIV infection

Question 18

Sickle-cell trait – protects against _______. Why?

Answer 18

RBCs that have some sickle-cell hemoglobin are not good hosts for the parasite that causes sickle-cell disease – thus the trait (heterozygote patient) is protective

However, the homozygote (all hemoglobin
is sickle-cell hemoglobin) is more vulnerable to the disease than the rest of the population

Question 19

mutations in structural proteins are more likely

Answer 19

dominant

Question 20

Enzyme defects are more likely

Answer 20

recessive

Question 21

autosomal mutations occur in

Question 22

how likely the mutated gene is to be expressed

Answer 22

Penetrance
So, if something is autosomal dominant but has a 50% penetrance, a heterozygote may only have a 50% chance of showing the disease phenotype

Question 23

how “much” the disorder-causing gene is
expressed

Answer 23

Expressivity
All heterozygotes still show the trait BUT the “intensity” of the trait differs from person to person

Question 24

___________ __________ disorders tend to involve genes that are part of metabolic pathways or regulation of these pathways

Answer 24

Autosomal dominant

Question 25

Disorders due to insufficient production of an enzyme tend to be _________

Answer 25

recessive

Question 26

Recessive disorders tend to be more severe than dominant disorders. Why?

Question 27

Gain of function mutations are _____ but can be autosomal dominant

Answer 27

rare

Question 28

disorder of connective tissues manifested principally by changes in the skeleton, eyes, and cardiovascular system

Answer 28

Marfan syndrome

Question 29

Marfan syndrome epidemiology: prevalence of __ in 5000

Answer 29

1 in 5000

Question 30

Etiology of Marfan syndrome. Is it dominant or recessive?

Answer 30

Disorder due to a defect in the gene for fibrillin-1
75 – 85% are familial; the rest are new mutations

Autosomal dominant
▪ chromosome 15
▪ 600 distinct mutations – most are missense

Question 31

____________ is an important component of elastic connective tissue, provides a “scaffold” for elastic fibre deposition

Answer 31

Fibrillin
Marfan syndrome is a disorder due to a defect in the gene for fibrillin-1

Question 32

Loss of fibrillin-1 explains many findings

Answer 32

• • i.e. aneurysm formation, ligamentous laxity, defects in eye structure
• Others are more difficult to explain
• Thought that increased skeletal growth is due to increased bioavailability of TGF-beta, which is affected by fibrillin levels (TGF-beta can also impact smooth muscle development)

Question 33

Prognosis of Marfan syndrome: Variable, main causes of mortality and morbidity are __________ and __________

Answer 33

aneurysms
valvular defects

Question 34

in autosomal recessive disorders, the expression of the defect tends to be more ________ than in autosomal dominant disorders.

Answer 34

uniform

Question 35

what are the following characteristics of?
▪ Complete penetrance is common
▪ Onset is frequently early in life
▪ they are rarely detected clinically

Answer 35

autosomal recessive

Question 36

In heterozygotes, _____ (equal/unequal) amounts of normal and defective enzyme are synthesized

Answer 36

equal

Question 37

Consequences of Enzyme Defects (3)

Answer 37

1. accumulation of a substrate (Sometimes the substrate can be toxic in high concentrations)
2. blockade of a metabolic pathway
3. failure to inactivate another enzyme or substrate

Question 38

Lysosomal storage disorders can be from a range of problems with lysosomal enzymes (3):

Answer 38

▪ Lack of the enzyme, leading up to a build-up of a substrate within a cell that is toxic

▪ Misfolding of the lysosomal enzyme

▪ Lack of a protein “activator” that binds to the substrate and improves the ability of the enzyme to act on it

at the of the day, you cannot have the reaction that the enzyme was catalyzing

Question 39

insoluble intermediates that accumulate in
the lysosomes

Answer 39

primary storage problem
occurs in lysosomal storage disease

Question 40

toxic effects from defective autophagy

Answer 40

secondary storage problem
occurs in lysosomal storage disease
▪ autophagy = “cellular housecleaning”

Question 41

Most common lysosomal storage disease. Between 1 in 20,000 and 1 in 40,000 live births. Autosomal recessive inheritance

Answer 41

Gaucher Disease

Question 42

Enzyme cleaves the glucose residues from ceramide, found in cell membranes

Answer 42

glucocerebrosidase

Question 43

Gaucher Disease is a defect in the gene for

Answer 43

glucocerebrosidase

• leads to accumalation of glucocerebrosidase in lysosome

Question 44

Gaucher Disease: involves organs outside the central nervous system – 99% of cases. Findings are mostly within the spleen
and bone. Enlargement of the spleen and liver. Weakened bones → frequent fractures

Answer 44

Type 1
Often relatively mild course

Question 45

Gaucher Disease: involves the CNS as well as
other organs. Hepatosplenomegaly and rapid
neurological deterioration, with
death in early childhood. CNS macrophage activation → production of toxic signals by macrophages → neuronal death

Answer 45

Type II

Question 46

All sex-linked disorders are __-linked, and the vast majority are _________

Answer 46

X
recessive

Question 47

A male with a mutant allele on his single X chromosome = ___________ for the allele

Answer 47

hemizygous

Question 48

Loss of function of a coagulation factor necessary for clotting

Answer 48

X-linked recessive – Hemophilia A

Question 49

Clinical Features of X-linked recessive – Hemophilia A

Answer 49

▪ Bruising and prolonged bleeding with minimal trauma
▪ Mucosal bleeding, hematomas in joint spaces (hemarthrosis)

Question 50

The person being “examined” (usually the one with a genetic condition) is known as the ________. indicated in the family tree by an ______

Answer 50

proband
indicated by an arrow