Genetics 11 - 20 Flashcards
Fragile X (prevalence and cause)
1/3500 males, 1/6000 females
Expanded CGG repeats in the FMRP 5’ UTR gene leads to hypermethylation and transcriptional shutdown
X-linked dominant inheritance (more common in males)
Fragile X clinical presentation
intellectual disability, autism spectrum, elongated faces, large ears, macroorchidism (large testicles)
Fragile X Associated Tremor/Ataxia Syndrome (FXTAS)
Late adult onset (over 50 usually). Will see Grandfathers have this - indicative of genetic anticipation
Causes tremor and ataxia (loss of control of body movements)
Fragile X Summary
Expanded CGG repeats -> hypermethylation of the FMRP 5’ UTR -> Loss of FMRP protein -> increased production of specific synaptic proteins (glutamate receptors) and loss of ability to regulate synaptic biology
** Example of DNA path
Myotonic Dystrophy Summary
Expanded CTG repeat -> Transcribed into expanded CUG repeats -> Sequestration of MBNL proteins -> Widespread changes in MBNL-mediated RNA splicing and RNA metabolism (the exon that is supposed to be excised isn’t!)
** Example of RNA path
Huntington’s Disease symptoms
Motor (chorea, delayed and reduced velocity, dystonia, rigidity), cognitive (difficulty searching memory, executive dysfunction), psychiatric (depressed mood, anxiety, irritability, increased risk for suicide)
Huntington’s Disease Summary
Expanded CAG repeat -> Transcribed and translated into polyglutamine repeats -> myriad of downstream consequences, protein aggregates, etc - > cell death (dramatic loss of striatal neurons in the brain)
** Example of protein path
Most common form of familial amyotrophic lateral sclerosis
C9ORF72/ALS/FTD
FTD = fronto-temporal dementia
C9ORF72/ALS/FTD
G4C2 and C4G2 antisense transcripts are produced. These transcripts form RNA foci.
Ribosomes initiate on these repeats without an AUG/start codon and various, toxic dipeptide repeats are created.
Still unknown whether its the toxic RNA, toxic protein, or both that contribute to the disease.
Most repeat expansion diseases are: dominant or recessive?
Dominant
Friedreich’s Ataxia is recessive
Hemoglobin S
Mutation in the beta-globin gene (valine for a glutamine)
Clinical manifestations of Sickle Cell Disease
Every organ in the body can be affected
- Anemia (reduced RBC life span, hemolysis)
- Vaso-occlusion most common clinical complication. No biomarkers to check for this. Believe the patient
- Vasculopathy (changes in the blood vessel wall)
- Strokes
- Loss of vision
- Acute chest syndrome
- Gallstones (cholelithiasis)
- Liver & kidney failure
- Splenic infarction (prevent with vaccinations and prophylactic antibiotics
- Leg ulcers
- Priapism (sustained erection)
Hydroxyurea
Used to treat SCD
Decreases painful episodes, hospitalizations, chest syndrome, and extends life
Acts by increasing the amount of HbF in the blood (exact mechanism unknown)
Clinical Interventions for SCD
immunizations, penicillin prophylaxis, stem cell transplant, RBC transfusions, hydroxyurea, L-glutamine powder
Heteroplasmy
More than one species of mitochondrial DNA per cell (mtDNA)
In dividing cells it leads to somatic mosaicism. When cells are partitioned during cytokinesis, some get higher levels of mutant mitochondria than others
Also often results from high mtDNA mutation rate
Homoplasmy
Uniformity of mitochondrial DNA (mtDNA)
How do mitochondrial diseases become established in families?
It’s a two generation process from mutated mtDNA to affected individual
If a blastomere with mutated mtDNA becomes a primordial germ cell, then the gamete of that individual will ultimately be affected
Mitochondrial diseases
About 40, very rare. Variable severity within families. Affects tissues with high energy requirements: muscle and nerve
Dosage compensation
Equalization of expression between XX and XY
X Chromosome inactivation happens when?
Occurs in blastomeres in early embryonic development
Random and irreversible. Decision is made independently in each cell
Mechanism of X inactivation
- Initiation (counting, selecting, inactivating)
* * The X chromosome bound by blocking factors (created by autosomes) remains active
* * Xist and Tsix compete (Xist prevails on inactive, Tsix prevails on active) - Establishment, spreading of inactivation from “inactivation center”
- Maintenance during subsequent mitotic divisions
Turner Syndrome
45,XO
Short stature, webbing of the neck, amenorrhea, normal intelligence
Klinefelter Syndrome
47, XXY
Tall, hypogonadism, some learning difficulties
Trisomy X (Triplo X)
47, XXX
Tall, variably reduced intelligence, may be fertile
What percentage of genes on the X chromosome normally escape X inactivation?
15%
What causes issues in Turner Syndrome (not enough gene product) and Trisomy X (too much gene product)
Basic Properties of Enzymes
- They enhance reactivity (acceleration reaction rate). ALWAYS to the same extent in forward and reverse directions
- They exert absolutely NO effect on the reaction equilibrium
- Lower the activation energy that reactants must surmount for a rxn to occur
Mutations in enzymes can affect:
- Rates of substrate binding
- pKa’s of catalytic ionic groups
- Metal ion interactions
- Rates of product release
- Conformational changes
NEVER RXN EQUILIBRIUM CONSTANT
A mutation that decreases Km will
Increase activity
Because it now takes less substrate to reach half maximal velocity
A mutation that increases Km will
Decrease activity
Because it now takes more substrate to reach half maximal velocity
Other enzyme mutational effects
- Change allosteric properties
- Alter enzyme polymerization
- Loss of organelle-targeting sequence
- Altered posttranslational modifications
Imatinib (Gleevec)
used in the treatment of CML (Philadelphia chromosome! 9 & 22)
Binds to the inactive form of the c-Abl protein kinase (in Bcr-Abl) and blocks cell motility. Very successful in long-term management of the disease, unless drug resistance mutations occur
Isozymes
Different proteins catalyzing same reaction
Alterations in T0 state stability
If T0 is much more stable than R0, then the molecule has a reduced affinity for O2. Harder to bind O2, easier to release. This shifts the O2 curve to the right (affinity for O2 has been reduced).
If T0 is slightly more stable than R0, than there is an increased affinity for O2. Easier to bind O2, but harder to release. This shifts the O2 curve to the left and makes it more hyperbolic (increased affinity for O2).
HbS polymerizes in the oxygenated or deoxygenated state?
Deoxygenated.
High metabolic activity lowers peripheral tissue pH and thus favors deoxygenation and then polymerization of a2BSBS
Polymerization requires homozygous HbS (aka no Sickle Trait)
What prevents irreversible fiber formation & sickling in SCD?
Delay in polymerization allows HbS to return to the lungs to get O2
Balanced polymorphism
condition where mutation leads to an advantage for the heterozygote but a disadvantage for the homozygote
ex: malaria resistance in Sickle Cell Trait
Major mediators of epigenetic effects
DNA methylation, chromatin modifications, non-coding RNAs
What maintains X inactivation?
DNA methylation
Sickle Cell Disease
Group of inherited blood disorders:
- Hb SS (sickle cell anemia)
- Hb S/B thalassemia
- Hb SC
Enzymes NEVER (even when mutated)
alter the reaction equilibrium constant
CFTR
Cystic Fibrosis Transmembrane-conductance Regulator
Phenylalanine deletion at position 508 found in 90% of CF patients
Protein fails to fold and cannot reach membrane
Hb genes are clustered on which chromosome?
16
Ways to biochemically confirm clinical indications of SCD
- Gel electrophoresis of an Hb sample
- High-performance liquid chromatography of alpha and beta chains
- Treat RBCs with dithionite to rapidly deoxygenate & then observe rate of sickling under a microscope
Fragile X Repeat
CGG
Myotonic Dystrophy Repeat
CTG
Huntington’s Disease Repeat
CAG
C9ORF72/ALS/FTD Repeat
G4C2 or C4G2
Is BRCA1/BRCA2 primarily germline or somatic mutation?
Germline
Family history questions for cancer screening
Cancer (age of onset, type, pathology), genetic testing, surgeries (breast, ovaries)
Where is genetics testing criteria found?
NCCN.org
What is the most common form of breast and ovarian cancer?
Sporadic
Genetic basis of Alveolar Capillary Dysplasia (ACD)
30-40% of cases due to mutation in the FOXF1 gene
Remaining cases have unknown cause
10% of cases have a familial association (usually siblings)
Alveolar Capillary Dysplasia
developmental anomaly of the pulmonary vasculature; “misalignment” of the pulmonary veins
Drapetomania
“disease” that caused slaves to run away from their masters
Buck vs. Bell
Supreme Court allowed Virginia’s involuntary steriliaztion law to stand
RNAi
RNA Interference
Technique to decrease mRNA levels of a target gene
siRNAs can be used to knockdown gene function
can have “off site” problems
miRNAs
non-coding, transcribed genes
mutations of miRNAs can lead to cancer & other diseases
mutations that create (or abolish) an miRNA binding site can cause disease (like TS)
possible targets for gene therapy
Benefits of RNAi
- very useful for studying gene function
- gene therapy
- fight off infection
- A number of products in clinical trials
miRNA pathway leads to
Imperfect match with mRNA and thus protein synthesis inhibition
RNAi pathway leads to
siRNA, perfect match with mRNA, and transcript degradation
Different between RNAi and miRNA?
RNAi is a lab technique. miRNA is encoded in our genes
Difference between RNAi and miRNA?
RNAi is a lab technique. miRNA is encoded in our genes
Can miRNA cause disease?
Yes!
Ex: Random point mutation results in the production of a novel miRNA binding site (Tourette’s Syndrome)
Only happens if the miRNA is expressed in the tissue where the protein is
myostatin
protein family that inhibits muscle differentiation and growth
elevated levels = little muscle growth
low levels = high muscle growth
Problems with RNAi therapy
- Delivery - getting it where you want it
- Off-target effects (sequence homologies can affect this)
- May induce subsets of genes in the immune response
Inheritance pattern of Fragile X
X-linked dominant
Inheritance pattern of Huntington’s Disease
Autosomal Dominant
Inheritance pattern of Myotonic Dystrophy
Autosomal Dominant
Lifespan of sickle RBC
10 - 20 days
120 is normal
What is the most common genetic disorder in the US?
Sickle Cell Disease
The sigmoidal curve of O2 binding to Hb is best explained by what?
Positive cooperatively - an increase in the availability of binding sites.
Majority of patients with ACD will have what other associated anomalies?
cardiovascular, gastrointestinal, urogenital, or musculoskeletal
Five major models that researchers use to explain racial inequalities in health
- socioeconomic status
- health behaviors
- psychosocial stress
- social structure and cultural context
- genetics factors contribute substantially to racial inequalities in health
Bio-psychosocial model
social and cultural factors have biological impacts beyond molecular genetic variation
Familial Pleuropulmonary Blastoma
rare pediatric lung tumor that is part of an inherited cancer syndrome (germline mutation in DICER1 halts miRNA creation and thus creates serious issues)
