Genetic Pathology Flashcards
2 types of substitutions and their interchanges.
1.) Transitions: purines (A,G) or pyrimidines (C,T) –> bases of similar shape (both 1 ring or both 2 ring)
2.) Transversions: purine for pyrimidine bases –> exchange of 1-ring and 2-ring structures
Frameshift mutation or frame shifting indels. Example?
all of the triplets are off by one.
ex. O blood type and LOF of the red blood cell antigen
ex. Tay-Sachs disease
Can the reading frame be preserved with insertion or deletion?
Yes, “non-frameshifting” indels–> if a multiple of 3 nucleotides are inserted or deleted.
ex: cystic fibrosis (deletion)
2 classifications of point mutations
silent or conservative missense point mut. =little or no change in function
non-conservative missense point mut. = significant change in function (sickle cells)
non-sense mutation
What happens if the triplet being changed becomes a stop codon?
Premature ending of translation = truncated (shortened) protein = non-sense mutation
ex. beta-thalassemia
What is the mutation that protects against HIV?
HIV uses a chemokine receptor, CCR5, to enter cells; a deletion in the CCR5 gene thus protects from HIV infection
What mutation protects against malaria?
Sickle-cell trait: SOME is good, ALL is bad
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 rest of the population
What are mendelian disorders?
Mutations in single genes=LARGE effect
80-85% familial
everyone has 5-8 non-beneficial gene mutations
Can be dom, rec, or codom.
X-linked, autosomal
Autosomal dominant disorders
STRUCTURAL PROTEINS
HETERrozygous or HOMOzygous
Usually have at least one parent with the disorder
Exception= spontaneous mutation
New mutations more common when father is older
Usually manifests in each generation
What is the term for how likely the mutated gene is to be expressed?
penetrance
if something is autosomal dominant but has a 50% penetrance, a heterozygote may only have a 50% chance of showing the disease phenotype
What is the term for how “much” the disorder-causing gene is expresed
expressivity
All heterozygotes still show the trait
The “intensity” of the trait differs from person to person
What do most autosomal dominant disorders lead to?
a protein that has reduced function or produced less
Marfan syndrome
disorder of connective tissues = changes in the skeleton, eyes, and cardiovascular system
Etiology: LOSS OF FIBRILLIN-1
Disorder due to a defect in gene for fibrillin-1
75 – 85% are familial; the rest are new mutations
Autosomal dominant
chromosome 15
600 distinct mutations – most are missense
Tall, with very long extremities and lax ligaments, weak heart valve
Autosomal recessive disorders
ENZYME DEFECTS
Largest category of Mendelian disorders
Basic rules of Mendelian inheritance apply
The expression of the defect tends to be MORE INFORM than in autosomal dominant disorders.
Complete penetrance is common.
Onset is frequently EARLY IN LIFE
HETERozygote
Many of the mutated genes encode enzymes
In heterozygotes, equal amounts of normal and defective enzyme are synthesized
Consequences of enzyme defects (aut. rec.)
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
i.e. alpha-1 anti-trypsin deficiency
Lysosomal storage diseases (aut. rec.)
1.) Lack of the enzyme, leading up to a build-up of a substrate within a cell that is toxic
2.) Misfolding of the lysosomal enzyme
3.) Lack of a protein “activator” that binds to the substrate and improves the ability of the enzyme to act on it
Difference between primary and secondary storage problems? (lysosomal storage diseases)
Primary- incomplete catabolism (accumulation of insoluble intermediates that accumulate in the lysosome
Secondary- defective autophagy (housecleaning)
What is the most common lysosomal storage disease?
Gaucher disease= defect in gene for glucocerebrosidase
Enzyme cleaves glucose residues from ceramide, found in cell membranes= glucosylceramide accumulates in lysosomes
Metabolites accumulate and can lead to the activation or loss of function of the phagocytes
Gaucher disease: type I vs type II
type I - organs outside CNS (99% of cases)
SPLEEN AND BONE
Enlargement of the spleen and liver
Weakened bones = frequent fractures
type II- involves the CNS as well as other organs
Hepatosplenomegaly and rapid neurological deterioration, with death in early childhood
production of toxic signals by macrophages = neuronal death
All sex-linked disorders are what?
X-linked
Are most sex-linked disorders recessive or dominant?
recessive
Features of x-linked disorders
Males with mutations affecting the Y-linked genes are usually infertile, and hence there is no Y-linked inheritance
Features:
An affected male does NOT TO SONS, but ALL DAUGHTERS=carriers
Sons of heterozygous women have a 1 in 2 chance of receiving the mutant gene
The heterozygous female usually does not express the full phenotypic change because of the paired normal allele
Gene carried on the X chromosome and usually only manifests in males
A male with a mutant allele on his single X chromosome = hemizygous for the allele
X-linked recessive inheritance:
transmitted by healthy heterozygous female carriers to affected males
affected males to their obligate carrier daughters
consequent risk to male grandchildren through these daughters
affected males can’t transmit to sons
X-linked recessive chart
X-linked recessive- Hemophilia A
LOF of coagulation factor nec. for CLOTTING=bleeding risk
Bruising and prolonged bleeding with minimal trauma
Mucosal bleeding, hematomas in joint spaces (hemarthrosis)
What is the person being examined/usually the one with the gen. condition called?
proband
What is the diagram called that traces how genetic diseases “appear” in families?
pedigree drawing
Does consanguinity increase or decrease the risk of autosomal recessive disorders manifesting?
increases
Can parents of affects proband not be affected?
Yes, often
T/F:
If only males are affected, a generation will be skipped.
true
