Basic Genetic Pathology Flashcards
____ of spontaneous abortions/miscarriages have a chromosomal abnormality
50%
__ of those under age 25 develop a disease with a significant genetic component
5%
Estimated that lifetime frequency is ___/1000
670
3 types of point mutations:
- substitution
- insertion
- deletions
all involving changes at one (or very few) nucleotides
Substitutions can be:
Transitions
Transversions
-interchanges of purines (A, G) or of pyrimidines (C, T)
- involve bases of similar shape (both one ring or both two ring)
Transitions
-interchanges of purine for pyrimidine bases
- involve an exchange of one-ring and two-ring structures
Transversions
Insertions or deletions of single nucleotides can lead to _________ mutations – all of the triplets are off by one. What are these often called?
frameshift
“frame-shifting indels”
What does a frame-shift mutation often result in?
Often results in total loss of function of the protein:
“O” blood type results from a ________ mutation and loss of function of the red blood cell antigen
frameshift
non-frameshifting “indels”
▪ If a multiple of three nucleotides are inserted or deleted, then the reading frame is preserved
Example – most common cystic fibrosis mutation
One nucleotide deletion –
frameshift would result in
Protein is no longer functional
Three nucleotide deletion –
non-frameshift would result in? This is the most common mutation in _________
loss of an amino acid
Most common mutation in cystic fibrosis
point mutation = little or no change in function
Silent or conservative missense
Point mutation: a significant change in function. What is an example?
nonconservative missense
Example – sickle cell anemia
If the nucleotide triplet being changed becomes a stop codon, then premature ending of translation. What would this result in?
non-sense mutation
truncated (shortened) protein
Example – some types of thalassemia
what is an example of nonsense?
beta-thalassemia
explain how due to a mutation, some people can’t be infected by the HIV virus
HIV uses a chemokine receptor, CCR5, to
enter cells; a deletion in the CCR5 gene
thus protecting from HIV infection
Sickle-cell trait – protects against _______. Why?
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
mutations in structural proteins are more likely
dominant
Enzyme defects are more likely
recessive
autosomal mutations occur in
how likely the mutated gene is to be expressed
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
how “much” the disorder-causing gene is
expressed
Expressivity
All heterozygotes still show the trait BUT the “intensity” of the trait differs from person to person
___________ __________ disorders tend to involve genes that are part of metabolic pathways or regulation of these pathways
Autosomal dominant
Disorders due to insufficient production of an enzyme tend to be _________
recessive
Recessive disorders tend to be more severe than dominant disorders. Why?
Gain of function mutations are _____ but can be autosomal dominant
rare
disorder of connective tissues manifested principally by changes in the skeleton, eyes, and cardiovascular system
Marfan syndrome
Marfan syndrome epidemiology: prevalence of __ in 5000
1 in 5000
Etiology of Marfan syndrome. Is it dominant or recessive?
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
____________ is an important component of elastic connective tissue, provides a “scaffold” for elastic fibre deposition
Fibrillin
Marfan syndrome is a disorder due to a defect in the gene for fibrillin-1
Loss of fibrillin-1 explains many findings
- 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)
Prognosis of Marfan syndrome: Variable, main causes of mortality and morbidity are __________ and __________
aneurysms
valvular defects
in autosomal recessive disorders, the expression of the defect tends to be more ________ than in autosomal dominant disorders.
uniform
what are the following characteristics of?
▪ Complete penetrance is common
▪ Onset is frequently early in life
▪ they are rarely detected clinically
autosomal recessive
In heterozygotes, _____ (equal/unequal) amounts of normal and defective enzyme are synthesized
equal
Consequences of Enzyme Defects (3)
- accumulation of a substrate (Sometimes the substrate can be toxic in high concentrations)
- blockade of a metabolic pathway
- failure to inactivate another enzyme or substrate
Lysosomal storage disorders can be from a range of problems with lysosomal enzymes (3):
▪ 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
insoluble intermediates that accumulate in
the lysosomes
primary storage problem
occurs in lysosomal storage disease
toxic effects from defective autophagy
secondary storage problem
occurs in lysosomal storage disease
▪ autophagy = “cellular housecleaning”
Most common lysosomal storage disease. Between 1 in 20,000 and 1 in 40,000 live births. Autosomal recessive inheritance
Gaucher Disease
Enzyme cleaves the glucose residues from ceramide, found in cell membranes
glucocerebrosidase
Gaucher Disease is a defect in the gene for
glucocerebrosidase
- leads to accumalation of glucocerebrosidase in lysosome
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
Type 1
Often relatively mild course
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
Type II
All sex-linked disorders are __-linked, and the vast majority are _________
X
recessive
A male with a mutant allele on his single X chromosome = ___________ for the allele
hemizygous
Loss of function of a coagulation factor necessary for clotting
X-linked recessive – Hemophilia A
Clinical Features of X-linked recessive – Hemophilia A
▪ Bruising and prolonged bleeding with minimal trauma
▪ Mucosal bleeding, hematomas in joint spaces (hemarthrosis)
The person being “examined” (usually the one with a genetic condition) is known as the ________. indicated in the family tree by an ______
proband
indicated by an arrow
