Principles of genetic disorders Flashcards
What are the four types of genetic disorders?
- Frame shift
- Point mutation
- Trinucleotide-repeat mutations
- Mutations within noncoding sequences
What are the three types of point mutations?
Substitution:
ex) THE FAT CAT ATE THE RAT; THE FAT HAT ATE THE RAT
Insertion:
ex) THE FAT CAT ATE THE RAT; THE FAT HCA TAT ETH ERA T
Deletion:
ex) THE FAT CAT ATE THE RAT; THE FAT ATA TET HER AT
(The C is missing)
Substitutions can be:
1) Transitions: interchanges of purines (A,G) or of pyrimidines (C,T)
-Involves bases of similar shape (both one ring or two ring)
2) Transversions: interchanges of purines for pyrimidine bases
-Involves exchange of one ring and two ring structures
Insertions or deletions can lead to what?
Frameshift mutations: All of the triplets are off by one (frame-shifting indels)
Often results in total loss of function of the protein:
-“O” blood type results from a frameshift mutation and loss of function of the red blood cell antigen
- Tay-Sachs disease
What happens if a multiple of three nucleotides is inserted or deleted:
The reading frame is preserved: non-frameshifting indels
ex) cystic fibrosis mutation
What type of deletion is this?
One nucleotide deletion: frameshift
-protein is no longer functional
What type of deletion is this?
Three nucleotide deletion: non-frameshift, but loss of amino acid
ex) cystic fibrosis
What type of point mutation has little or no change of funtion?
Silent or conservative missense
What type of point mutation has significant change in function?
nonconservative missense
ex) sickle cell anemia
Describe a non-sense point mutation:
Nucleotide triplet being changed becomes a stop codon, then there is a premature ending of translation-> truncated (shortened) protein.
What type of point mutation is this?
Non-conservative missense
-sickle-cell anemia
What type of point mutation is this?
Nonsense
-beta-thalassemia
Some people can’t be infected with the HIV virus because of mutations, what type of receptor does HIV use, and what type of mutation happens to protect an individual form HIV?
HIV uses chemokine receptor, CCR5, to enter cells; a deletion in the CCR5 gene thus protects from HIV infection
What does the Sickle-cell trait protect against?
Malaria:
RBC’s 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
What are the types of genetic disorders?
Mendelian disorders:
Autosomal mutations: -Dominant: structural proteins (Marfan's syndrome-structural protein deficit)
-Recessive: Enzyme defects (Lysosomal storage diseases)
X-Linked disorders: -Hemophilia
Due to mutations in single genes that have large effects:
-Thought that everyone has 5-8 non-beneficial gene mutations (Most of these have relatively small effects on phenotype)
-80-85% familial, rest are new mutations:
This can differ depending on the type of disorder: 80% of those with achondroplasia (defect in elongation of the bone growth plate) are new mutations
-Traits can be dominant, recessive, or codominant
-Manifested in heterozygous or homozygous state
-Usually have at least one parent with the disorder:
Exception: spontaneous mutation occurs
New mutations: more common when father is older
-Usually manifests in each generation
Autosomal dominant disorders
How likely the mutated gene is to be expressed:
Penetrance (autosomal dominant disorder)
explained: If something is autosomal dominant but has 50% penetrance, a heterozygote may only have a 50% chance of showing the disease phenotype.
How “much” the disorder-causing gene is expressed:
Expressivity (autosomal dominant disorder)
-All heterozygotes still show the trait
-The intensity of the trait differs from person to person
True or False: Most mutations lead to a protein that has reduced function or is produced less (loss of function mutation)
True
What to autosomal dominant disorders tend to involve?
Genes that are part of metabolic pathways or regulation of these pathways
-some involve defects in structural proteins
Disorders due to insufficient production of an enzyme tend to be recessive. Why?
This pattern of inheritance helps explain why some genetic disorders related to enzyme deficiencies are more commonly observed in individuals who have inherited two mutated alleles, which is a recessive trait. The carriers (heterozygous individuals) can pass on the mutated allele in the population without displaying the disorder themselves.
Gain of function mutations are ______, but can be ____________________.
rare; autosomal dominant
Autosomal dominant disorders:
study!
Disorder of connective tissues, manifested principally by changes in the skeleton, eyes, and cardiovascular system
Epidemiology: prevalence of 1 in 5000
Etiology: 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
Pathophysiology: Fibrillin is an important component of elastic connective tissue, provides a “scaffold” for elastic fiber deposition
-Loss of fibrillin-1 explains many findings:
ex) 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)
Marfan Syndrome
What are the clinical findings and prognosis of Marfan syndrome?
Clinical findings:
-Tall, with very long extremeties and lax ligaments
-Dislocation of the lens
-Cardiovascular changes; Mitral valve prolapse-malformed and “weak” heart valve
-Weakness in the muscular layers of the aorta, which can lead to aortic valvular incompetence and development of serious aneurysms
-Variability expressivity; Some individuals may lack certain clinical findings. ex) skeletal findings with no ocular findings
Prognosis: Variable, main causes of mortality and morbidity are aneurysms and valvular defects.
-Surgical repair of aneurysms, heart valves
-Largest category of Mendelian disorders
-Basic rules of Mendelian inheritance apply
As well:
-The expression of the defect tends to be more uniform than is autosomal dominant dosorders
-complete penetrance is common
-Onset is frequently early in life
-Although new mutations associated with recessive disorders do occur, they are rarely detected clinically, since the individual with a new mutation is an asymptomatic heterozygote
-Many of the mutated genes encode enzymes
In heterozygotes, equal amounts of normal and defective enzyme are synthesized.
Usually that natural “margin of safety” ensures that cells with half the usual complement of the enzyme function normaly.
Autosomal recessive disorders
Consequences of enzyme defects:
Accumulation of a substrate:
-Sometimes the substrate can be toxic in high concentrations
Blockage of a metabolic pathway
Failure to inactivate another enzyme or substrate:
ex) alpha-1 anti-trypsin deficiency
Can be from a range of problems with lysosomal enzymes:
-Lack of the enzyme, leading up to build-up of a substrate within a cell that is toxic.
-Misfolding of the lysosomal enzyme
-Lack of protein “activator” that binds to the substrate and improves the ability of the enzyme to act on it.
Lysosomal Storage diseases
Pathophysiology of lysosomal diseases:
-In the example shown, a complex substrate is normally degraded by a series of lysosomal enzymes (A,B, and C) into soluble end products
-Deficiency or malfunction of one of the enzymes (ex B) -> incomplete catabolism-> insoluble intermediates that accumulate in the lysosomes-> “primary storage” problem
-Huge, numerous lysosomes interfere
with cellular function
-Second storage Problem= toxic effects from defective autophagy.
What is autophagy?
“cellular housecleaning”
Most common lysosomal storage disease
-Between 1 in 20,000 and 1 in 40,000 live
births.
-Autosomal recessive inheritance
Defect in the gene for glucocerebrosidase
-Enzyme cleaves the glucose residues from
ceramide, found in cell membranes.
-Glucosylceramide accumulates in
lysosomes.
Metabolites accumulate mainly within macrophages and other phagocytic cells as the phagocytose dying cells and metabolize the membranes.
-This can lead to the activation or loss of
function of the phagocytes.
Gaucher Disease
Gaucher Disease Type I:
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
Gaucher disease Type II:
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.
All sex-linked disorders are ___________, and the vast majority are ____________.
x-linked; recessive
Males with mutations affecting the y-linked genes are usually ___________, and hence there is no y-linked inheritance.
infertile
Features of x-linked disorders:
An affected male does not transmit the disorder to his sons, but all daughters are 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 chromosomes 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.
Hemophilia A:
Loss of function of a coagulation factor necessary for clotting.
-Affects over 20,000 men in North America
-Different mutations confer different
bleeding risk-thousands of mutations have
been identified with variable impacts on
coagulation.
Clinical features:
-Bruising and prolonged bleeding with minimal trauma.
-Mucosal bleeding, hematomas in joint spaces (hemarthrosis)
The person being “examined” (usually the one with the genetic condition) is known as the__________
proband
Diagram developed around the proband is called:
Pedigree
Frequent appearance of the disease throughout generations:
Autosomal dominant pedigree
May not show a typical 50% chance of transmission (remember reduced penetrance)
Affects both males and females
Autosomal recessive pedigree
The risk of autosomal recessive disorders manifesting increases if there is consanguinity.
-If a homozygote has offspring with a
heterozygote, can also look deceptively
frequent.
Often parents of affected proband not affected.
Only males appear affected.
Trait is never passed from father to son
May see “knight’s move” pattern of transmission.
X-linked recessive pedigree
