8/8/17 Flashcards
Osteogenesis Imperfecta
Type I: fractures of arm and leg bones, heal normally, have half of normal procollagen amount so Loss of Function mutation, blue sclera
Type II: bunch of bone fractures at birth, die soon, mutant collagen
Dominant negative LOF mutation
Substitute Gly in collagen
Achondroplasia
Autosomal dominant, fibroblast growth factor 3 (FGFR3)
Mutation so stabilize FGFR3 dimers, constitutively activate a negative regulator, increase with dad age
Anticipation
Occurrence of genetic disease at an earlier age of onset and with increasing severity in successive generations
Triplet repeats tend to expand, intron is FA
Huntington’s Disease
Autosomal dominant, high penetrance
Personality changes, motor probs, memory loss
Caused by polyglutamine mutation
Initial: impaired muscles, forgetful, personality change
Middle: involuntary and voluntary uncontrolled, slur speech, depress and crazy
End: immobile, mind is nonfunctional
Duchenne Muscular Dystrophy
1/3 are point mutations and insertions
Haldane Hypothesis
X-linked disorder
Myofibe degeneration and regeneration with adipose and connective tissue, calf pseudohypertrophy
Cardiomyopathy, retarded, die early
Dystrophin protects striated muscle membranes from damage by linking actin to ECM, is absent in DMD
Haldane Hypothesis
1/3 of mutant alleles are lost each gen in X-linked, if disease frequency is constant then 1/3 must be new mutations
Becker muscular dystrophy
Mutations in dystrophin gene but milder and onset
Spinal muscular atrophy
Autosomal recessive, LOF of SMN1
Muscle atrophy, SMN1 has a deletion that prevents it from making 90% of SMN transcript so SMN2 (with a single base change from SMN1) makes a small amount
Severity depends on SMN2 copy number
Type 1: Werdnig-Hoffman disease, floppy muscles and breathing probs, die before 2
Type 2: sit but not stand, die as a kid
Type 3/4: milder, adult survival
SMA treatments
Spinraza: exon skipping to include exon 7, intrathecal
Avexis: gene therapy, intravenous
Better motor milestones than SMA Type 1
Allelic heterogeneity
Locus heterogeneity
Clinical heterogeneity
Multiple Diff mutations in same allele
Mutations in more than one gene
Diseases have diff phenotype but caused by same phenotype
Mitochondrial diseases
Affect high aerobic tissues like eyes, nervous system, cardiac, and muscles
Leber hereditary optic neuropathy, MERRF, and MELAS
Affected males don’t transmit to kids
Satellite DNA
Alpha-satellite: kinetochores of all chromosomes
Beta-satellites: variable regions of 1,9,Y, and acrocentrics
SNP
A change in DNA that occurs in at least 1% of the population
Responsible for most variation in gene expression
UV Radiation Effect
Thymine dimers that need nucleotide excision repair
Alkylation and cross linking agents
Cytoxan and tobacco
Add methyl to G and may cross link DNA strands
Demaminatin of C
Converts to U so one strand binds with A instead of G
ROS
Makes 8-oxoguanine
Now pairs with A or C
Fragile X Syndrome
Retarded, big ears and jaw, big balls
Triplet repeat mutation, RNA binding protein (FMRP) for translation regulation and synaptic plasticity plasticity
5’CGG repeat gets enlarged during maternal meiosis which causes miRNAs to methylated the 5’CpG island, only occurs after a certain CGG repeat size threshold
Example of anticipation
GOF: trigger miRNA release
LOF: transcription shuts down for the neuroplastic gene
Red-green color blindness
Red and green located on X chromosome
Unequal crossing over
Hemoglobin Lenore
Fusion of beta globin genes due to unequal crossing over
Delta beta fusion
Dominant Negative Mutation (LOF)
Heterozygous alleles
Mutant polypeptide loses own function AND interferes with function of the normal allele
More than 50% reduction in function
RET GOF mutation
Transmembrane receptor with tyrosine kinase domains that activate MAPK pathway for transcription
Can cause Multiple Endocrine Neolasia 2, a thyroid cancer
Missense mutations that that cause excess reaction to ligand, constitutively active receptors, overproduction of neuroendocrine cells
Changes to Cys a big thing
GOF mutation
Friedrich Ataxia
GAA repeats in intron
GOF: heterochromatin formation
LOF: transcription shit down
Myotonic dystrophy
CTG in 3’ UTR
GOF: attract RNA binding proteins from extra RNA, abnormal splicing of other gene transcripts like insulin receptor and muscle chloride channel
LOF: other transcripts
Open, triangular shaped mouth in baby
Weird face
Base excision repair
Fix most common DNA damage, purine loss and 8-oxoguanine
MUTYH involved in 8-oxoguanine repair
LOF muatins lead to colorectal cancer
Xeroderma pigmentosum
Nucleotide excision repair prob
Skin and eyes sensitive to UV, get skin cancer
Autosomal recessive
Complementation
Single allele mutations in two diff loci don’t produce disease
Mismatch repair
Replication errors like mismatch nucleotides, microsatellites
MLH1/PMS2 and MSH2/MSH6 recognize mismatch and recruit other repair machinery like EXO1
Lynch Syndrome
Hereditary nonpolyposis colorectal cancer
Defective base mismatch repair leads to cancers like colorectal and ovarian
Mutations in 4 mismatch repair genes plus EPCAM, which prevents transcription of MSH2
DsDNA damage signal and repair syndromes
Maintenance of structure and integrity of DNA (helicase): Bloom syndrome
Signal the repair process: ataxia telangiectasia
Locate damage and trigger repair: Fanconi anemia
Repair of DNA: BRCA 1 and 2
End-joining of dsDNA: Nijmegen breakage syndrome
Bloom syndrome
Maintenance: suppression of recombination
DNA RecQ helicase
Predisposed to most cancers, excess sister chromatid exchanges that can lead to unbalanced exchanges
Short stature
Ataxia telangiectasia
Signals BRCA of chromatin changes like by ionizing radiation
Difficulty with movements and chromosomal instability, cancer
Franconia anemia
LOF recessive
Sensitive to DNA damage like cross links
Short stature,skin hyperpigmentation, malformed kidneY and limb, bone marrow failure
Locate and trigger
Nijmegen breakage syndrome
Super rare
Short, progressive small head, immunodeficiency, and increased non-Hodgkin lymphoma
End joining of dsDNA
HereditRy breast/ovarian cancer syndrome
Single LOF mutation, autosomal dominant phenotype (only non biallelic LOF recessive)
Higher breast and ovarian cancer plus prostrate in dudes
SsDNA break repair
PARP1: poly[ADP-ribose]polymerase 1
PARP1 inhibitor for chemo for BRCA mutation: eliminating one DNA repair pathway leads to genome instability like cancer, eliminating both repair pathways leads to cell death
Nuclear transport
Prospective protein has a positive nuclear localization signal that binds to nuclear import receptor, nuclear import receptor moves down cytosolic fibrils and releases protein
Mitochondrial transport
Precursor protein with positive N terminal signal sequence binds to the import receptor protein, protein unfolded to be threaded through intermembrsne space and past protein translocator in inn
Ribosome location
Proteins destined to be translated on ER-bound ribosomes have ER import sequence, located on N terminus
Signal recognition particle binds to ER signal sequence and then binds to SRP receptor on ER
Stay in cytosol if have no ER import signal sequence
ER embedded proteins
Protein threaded through protein translocator until hit hydrophobic stop transfer sequence, spit out, signal peptidase cleaves N terminal signal sequence
Swyer Syndrome
XY gonadal dysgenesis
Mutation in SRY
Normal guy karyotype but external female genitalia without ovaries
SRY is a TR that initiates sex determination in embryogenesis
Can be from mutations in nuclear localization signal of SRY
Alpha thalassemia
Deletions of 1-4 alpha globin genes
3 deleted copies gets kinda serious, Hemoglobin H disease
4 deleted is Hemoglobin Bart’s with 4 gamma subunits, neonatal death
Beta Thalassemia
Many different types of mutations cause this
Thalassemia major is Cooley’s anemia, with enlarged organs and bones deformed
Heinz body hemolytic anemias
Point mutation in Beta subunit
Denature Hb molecule
Coagulation in the erythrocyte
Better to have increased or decreased oxygen affinity?
Decreased since increased is more severe
Sickle Cell anemia
Single point mutation (Hb S) changes Glu to Val (BGlu6 to Val)
Hydrophobic patch makes sticky in T state and polymerize
Hemoglobin C
Glu6Lys
West Africa
Milder anemia due to reduction in RBC lifespan
Not bad Hb variants
Hb E and Hb I
Involve point mutations that have AA with opposite charge
Both variants arose independently
Hb glycosylation
Not enzymatic, proportional to glucose conc.
Used for HbA1c levels
Little effect on function
Levinthal’s Paradox
10 possible conformations for each AA
Proteins can’t fold randomly because it would take ridiculously long, so a predetermined path must exist
Foldon
Units that fold in a single cooperative step
Secondary structure elements
Anfinsen Conclusions
Info for folding is in primary structure
Folding is thermodynamically controlled, no need for energy
Consequences of Excluded Volume Effect
Increase: effective conc., asosociation rate constants of large molecules, Rate of aggregation
Decrease apparent solubility
Proteins at risk for aggregating
Names can’t chains synthesized from polysomes: growing chains close together not fold but aggregate
Nuclear proteins: crowded and charged macromolecules
Mutant proteins:
Unfolded proteins under environmental stress like heat
Foldases
Catalyze rate-limiting step in folding
Peptidyl-prolyl CIA trans isomerase
PPI
Accelerates folding cuz catalyze CIA and trans isomer conversions of Pro peptide bonds
Protein disulfide isomerase
Catalyze disulfide interchange reactions, which is rate limiting in ER lumen
Localized to ER
Anfinsen Cage
Sequester polypeptide to prevent aggregation and provides appropriate folding environment
Found in chaperonin
Systemic amyloidosis
Extra cellular deposition and accumulation of insoluble protein
Amyloid have beta sheet structures that cross link
Transthyretin binds and transports thyroid hormone and vitamin A through the body
Alpha-1-antitrypsin deficiency
AATD
Alpha-1-antitrypsin is stuck in liver and can’t go to lungs, helps protect lungs from neutrophil elastase
Caused by incomplete folding or aggregation
Alzheimer’s disease
Beta amyloid plaques
Example of localized amyloidosis
Secretase cuts APP (a large precursor protein) to form beta amyloid
Abnormal postranslational modifications of precursor proteins
Molecular chaperones
Decrease rate of aggregation
Can work in tandem
Some require ATP
Prevent inappropriate interactions among proteins
Prions
Infectious agents composed of misfiled proteins
Spongiform encephalopathy
