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179 Cards in this Set
- Front
- Back
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Who are the histones and what do they do?
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H1 - ties nucleosomes together
H2A, H2B, H3, H4 form octamer that DNA coils around = nucleosome |
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Heterochromatin vs Euchromatin?
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Hetero= highly condensed, inactive
Eu=less condensed, active |
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G-C vs A-T bonds?
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G-C's are stronger, so if you increase G-C's you'll increase melting point
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What is needed to make a Pyrimidine?
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Aspartate (3 C's and 1 N)
Carbamoyl Phosphate (1 C, 1 N) |
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What is needed to make a Purine?
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Aspartate (1 N)
Glycine (2 C's, 1 N) Glutamine (2 N's) CO2 (1 C) N-Formyl-tetrahydrofolate (2 C's) |
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Nucleoside vs Nucleotide?
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side = base + ribose
tide = base + ribose + phosphate; link by PDE bond |
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Enzyme needed to get from ribonucleotide to deoxyribonucleotide?
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Ribonucleotide reductase
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Drugs that interfere w/ nucleotide synthesis?
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Hydroxyurea
6-mercaptopurine 5-fluorouracil Methotrexate Trimethoprim |
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MOA for hydroxyurea?
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inhibits ribonucleotide reductase (so no Ribonucleotides-->deoxyribonucleotides)
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MOA for 6-mercaptopurine?
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blocks de novo PURINE synthesis
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MOA for 5-fluorouracil?
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inhibits thymidylate synthase
so dec dTMP |
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MOA for Methotrexate?
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Inhibits dihydrofolate reductase
dec dTMP |
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MOA for Trimethoprim?
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inhibits BACTERIAL dihydrofolate reductase (dec dTMP)
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Transition vs Transversion?
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Transition = switiching purine for purine or pyrimidine for pyrimidine
Transversion = switching purine for pyrimidine or vice versa |
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Difference between Unambiguous and Degenerate/Redundant genetic coding?
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Unambiguous = 1 codon for 1 AA
Deg/Redundant = multiple codons for 1 AA |
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Helicase is?
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Enzyme that unwinds DNA at replication fork
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Single Stranded Binding Proteins do?
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Prevent strands from reannealing
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DNA Topoisomerases do?
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Create a nick in the helix to relieve supercoils
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Primase does?
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Makes an RNA primer that DNA Pol III initiates replication upon
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DNA Polymerase III?
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ONLY PROKARYOTES
elongates leading strand by adding deoxynucleotides to the 3' end. Elongates lagging strand until it reaches primer of preceding fragment 3'-->5' exonuclease activity (proofreads 3'-->5', but synthesizes 5'-->3') |
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DNA Polymerase I?
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Prokaryotes only
Degrades RNA Primer (via 5'-->3' exonuclease) and fills in the gap w/ DNA |
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DNA Ligase?
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Seals it
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General MOA of Fluoroquinolones?
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Inhibit DNA Gyrase, a specific prokaryotic topoisomerase
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Single Strand DNA Repair Mechanisms?
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Nucleotide Excision Repair
Base Excision Repair Mismatch Repair |
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Double Strand DNA repair mechanisms?
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Nonhomologous End Joining
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Specific Diseases caused by Mutations in DNA Repair?
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Xeroderma Pigmentosum
Hereditary Nonpolyposis Colorectal Cancer |
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Who is mutated in Xeroderma Pigmentosum?
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NER
Prevents repair of thymidine dimers |
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Who is mutated in HNPCC?
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Mismatch Repair
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What direction are DNA and RNA synthesized in?
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5'-->3'
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What direction is mRNA read?
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5'-->3'
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What direction are proteins synthesized?
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N-->C
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Which RNA type is most abundant? longest? smallest?
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rRNA is most abundant (rampant)
mRNA is longest (massive) tRNA is smallest (tiny) |
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start codon?
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AUG
it all starts in the A U G |
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What does AUG code for?
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Methionine (formyl-met in prok's)
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Stop codons?
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UGA
UAA UAG |
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Who binds to the Promoter?
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RNA polymerase and other transcription factors
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Which RNA Pol makes which RNA (in eukaryotes)?
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RNA Pol I: rRNA
Pol II: mRNA Pol III: tRNA numbered as their products are used in protein synthesis |
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What is alpha-amanitin and what is its MOA?
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Death Cap Mushroom compound that inhibits RNA Pol II
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How do RNA Polymerases differ in prokaryotes?
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There's only 1 and he makes all the RNA
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What are the steps of RNA processing?
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1. Cap the 5' end (7-methylguanosine)
2. Polyadenylation of 3' end (200 a's) 3. Splicing out of introns |
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What is hnRNA?
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heterogenous nuclear RNA, i.e. pre-processing RNA. after processing --> mRNA
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How are introns spliced out?
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Primary transcript binds w/ snRNPs and other proteins to form spliceosome.
Lariat is formed Lariat is cut out. Non-lariat pieces are joined together |
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What is alternative splicing? disease correlation?
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different combo's of exons to make unique proteins
this is how you get different beta-thalassemia mutations |
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Structure of tRNA?
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Cloverleaf
Anticodon at one end 3' Aminoacyl group at other end |
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How does a tRNA get charged/
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Aminoacyl-tRNA synthetase
makes sure you get the right AA and then adds it to the 3' end |
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General Mechanism of Tetracyclines?
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bind the 30S subunit preventing the attachment of aminoacyl-tRNA
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what is up with tRNA wobble?
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tRNA and mRNA only need accurate pairing of the first 2 nucleotide positions. The 3rd position is thus the wobble position
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General Steps to Protein Synthesis?
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Initiation
Elongation Termination |
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Ribosomal subunits in Eukaryotes vs pro?
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Eu: (even) 40S + 60S = 80S
Pro: (odd) 30S + 50S = 70S |
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Ribosome sites for Elongation?
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A
P E |
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Which drugs work as protein synthesis inhibitors?
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Aminoglycosides
Chloramphenicol Macrolides Clindamycin |
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MOA for Aminoglycosides?
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inhibit formation of initiation complex and cause misreading of mRNA
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MOA for Chloramphenicol
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inhibit 50S peptidyltransferase (so new AA's aren't added to chain)
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MOA for Macrolides?
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bind 50S and block translocation
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MOA for Clindamycin?
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bind 50S, block translocation
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Energy Requirements for Translation?
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ATP--> AMP for tRNA Aminoacylation (2)
GTP-->GDP for loading tRNA on ribosome GTP-->GDP for translocation = 4 bonds |
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Posttranslational Modifications?
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Trimming (remove N or C propeptides)
Covalent Alterations Proteasomal Degradation (attach ubiquitin to defective proteins to tag for destruction) |
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Who regulates the Cell Cycle?
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CDK's
Cyclins Cyclin-CDK Complexes Tumor-Suppressors |
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Stereotypical Tumor Suppressors?
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p53
Rb they inhibit G1-->S |
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Types of Cells, the stages of the cell cycle they like, and examples?
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Permanent: remain in G0, Neurons, Muscle, RBC's
Stable: enter G1 when stimulated, Hepatocytes, lymphocytes Labile: never go to G0, marrow, gut epithelium, skin, hair follicles |
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What occurs in the RER vs Smooth ER?
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RER: Synthesis of Secretory proteins. Addition of N-oligosac to proteins
SER: Steroid synthesis and detox of drugs and poisons |
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Special RER in neurons?
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Nissl Bodies
synthesize enzymes and peptide neurotransmitters |
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what do Free ribosomes do?
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synthesis of cytosolic and organellar proteins
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So where would you expect to find cells with lots of SER?
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Hepatocytes
Cells in adrenal cortex |
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Fxns of the Golgi Apparatus?
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Distribution of proteins to plasma membrane, lysosomes, and secretory vesicles
Modifies N-oligosac on asparagine Add's O-oligosac to serine and threonine Adds mannose-6-phosphate to specific lysosomal proteins Proteoglycan assembly from core proteins Sulfation of sugars in proteoglycans and of tyrosine on proteins |
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Vesicular Trafficking Proteins?
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COPI
COPII Clathrin |
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Role of COPI?
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Retrograde: Golgi-->ER
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Role of COPII
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Anterograde
RER-->cis-Golgi |
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Role of Clathrin?
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trans-Golgi-->lysosomes, plasma membrane-->endosomes (Rec-mediated endocytosis)
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What is up with I-cell Disease?
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Inclusion Cell Disease
inherited lysosomal storage disorder Failed addition of mannose-6-phosphate-->enzymes released out of cell instead of into lysosome |
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Sx's of I-Cell disease?
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Coarse Facial Features
Clouded Corneas Restricted Joint Movement High Plasma Levels of Lysosomal Enzymes often fatal in childhood |
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Structure of Microtubules?
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Cylindrical
Helical array of polymerized dimers of alpha and beta-tubulin |
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Where do you find microtubules?
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Flagella
Cilia Mitotic Spindles Slow axoplasmic transport in neurons |
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What the crap are Molecular Motor Proteins?
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Transport proteins that cellular cargo toward opposite ends of microtubule tracks
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Who are the Molecular Motor Proteins?
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Dynein: retrograde movement (+ --> -)
Kinesin: anterograde (- --> +) |
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Drugs that act on Microtubules?
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Mebendazole/Thiabendazole (antihelminthic)
Griseofulvin (antifungal) Vincristine/vinblastine (anti-cancer) Paclitaxel (anti breast cancer) Colchicine (anti-gout) |
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What is up with Chediak-Higashi Syndrome?
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Microtubule polymerization defect --> decreased phagocytosis
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Sx's of Chediak-Higashi Syndrome?
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Recurrent pyogenic infections
Partial Albinism Peripheral Neuropathy |
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Cilia Structure
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9 + 2
Axonemal Dynein |
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Role of Axonemal Dynein?
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ATPase that links peripheral 9 doublets and causes bending of cilia
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What's up with Kartagener's Syndrome?
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Immotile cilia due to dynein arm defect
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Sx's of Kartagener's?
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Male and Female Infertility
Bronchiectasis Recurrent Sinusitis Associated w/ situs inversus |
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Who are the Cytoskeletal Elements?
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Actin and Myosin
Microtubules Intermediate Filaments |
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Where do you find Actin and Myosin
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Microvilli
Muscles Cytokinesis Adhering junctions |
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Where do you find Intermediate Filaments?
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Vimentin
Desmin Cytokeratin Glial fibrillary acid proteins (GFAP) Neurofilaments |
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Make-up of Plasma Membrane?
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50% cholesterol
50% Phospholipids sprinkling of proteins, sphingolipids, glycolipids |
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What does increasing cholesterol or long, saturated FA's in the membrane do to the cell?
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Inc Melting Temperature
Dec Fluidity |
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What's up with Immunohistochemical Stains?
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You can stain for different intermediate filaments and subsequently determine the cell type
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IH stain and corresponding cell type?
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Vimentin:Connective Tissue
Desmin: Muscle Cytokeratin: Epithelial Cells GFAP: Neuroglia Neurofilaments: Neurons |
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Who is the membranous sodium pump?
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Na/K ATPase
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How does the plasma membrane Na/K ATPase work?
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For every ATP consumed, 3 Na's leave and 2 K come in
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MOA of Ouabain?
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Inhibits Na/K ATPase by binding the K site
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Who are the Cardiac Glycosides?
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Digoxin
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MOA of Digoxin?
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Directly inhibits Na/K ATPase-->indirect inhibition of Na/Ca exchanger--> inc Ca in cell--> inc contractility
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What is the most abundant protein in the body?
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Collagen
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Types of Collagen and their location?
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Type I (90%): bone, skin, tendons
Type II: Cartilage (including hyaline), etc. Type III: (Reticulin) Skin, vessels, uterus, etc Type IV: Basement Membrane |
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Steps of Collagen Synthesis
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IN FIBROBLAST
Synthesis (RER) Hydroxylation (ER) Glycosylation (ER) Exocytosis OUTSIDE OF FIBROBLAST Proteolytic processing Cross-Linking |
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What is made during Synthesis step?
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Preprocollagen: usually Gly-X-Y where X and Y are usually proline, hydroxyproline, or hydroxylysine
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What happens w/ hydroxylation?
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Hydroxylation of proline and lysine
REQUIRES VITAMIN C (think scurvy) |
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What happens w/ Glycosylation?
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Formation of Procollagen = triple helix of 3 alpha chains
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what happens w/ Proteolytic Processing?
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Cleavage of terminal regions of procollagen to get Tropocollagen
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What happens w/ Cross-Linking?
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Reinforcement of staggered tropocollagen molecules by lysine-hydroxylysine cross-linkage--> Collagen Fibrils
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Where does Osteogenesis Imperfecta screw things up?
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At glycosylation into procollagen triple helix
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Where in synthesis does Ehlers-Danlos screw things up?
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At the cross-linking stage
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Sx's of Ehlers-Danlos?
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Hyperextensible Skin
Tendency to Bleed (easy bruising) Hypermobile Joints |
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what type of collagen is affected w/ Ehlers Danlos?
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Type III is most commonly affected
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Osteogenesis Imperfecta is most commonly inherited how?
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Auto Dom
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Sx's of Osteogenesis Imperfecta?
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Multiple Fractures
Blue Sclera due to translucency of CT over the choroid Hearing Loss (abnormal middle ear bones) Dental Imperfections from lack of dentin |
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Kicker for Type II Osteogenesis Imperfecta?
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Fatal in utero or in neonatal period
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What causes Alport's Syndrome?
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Abnormal Collagen Type IV
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Most common inheritance pattern for Alport's?
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X-linked Recessive
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Sx's of Alport's?
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Progressive Hereditary Nephritis
Deafness Possibly ocular disturbances |
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Where do you find Elastin?
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Lungs
Arteries Elastic Ligaments Vocal Cords Ligamenta Flava (vertebrae connector) |
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Make-Up of Elastin?
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Non-glycosylated Proline and Glycine
Tropoelastin w/ Fibrillin Scaffoliding |
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Who breaks down elastin? who stops the breakdown?
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Elastase
Normally stopped by alpha1-antitrypsin |
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Two disorders affecting Elastin and their pathogenesis?
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Marfan's Syndrome: defect in fibrillin
Emphysema: can be caused by alpha1-antitrypsin deficiency-->excessive elastase activity |
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What's the premise for PCR?
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Amplify a desired fragment of DNA
Denature Anneal Elongate |
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Different Blotting procedures
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Souther Blot: labeled DNA probe for DNA
Northern Blot: labeled DNA probe for RNA Western Blot: labeled antibody binds to a Protein |
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What's up with a microarray?
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Thousands of nucleic acid sequences are arranged on a glass or silicon chip. DNA or RNA probes thrown on the chip and then its scanned to detect binding.
Can detect single nucleotide polymorphisms (SNPs) |
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What does ELISA test for?
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Antigen-Antibody Reactivity in patient's blood sample.
Can use a Test Ag or a Test Ab. Specificity and Sensitivity are near 100% |
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What's up with FISH?
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Fluorescent DNA or RNA probes search our certain genes.
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How can we clone DNA?
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1. DNA fragments are inserted into bacterial plasmids
2. Restriction enzymes cleave DNA in fragments that are inserted into a plasmid 3. Tissue mRNA is exposed to reverse transcriptase forming cDNA |
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What's up with Sanger DNA Sequencing?
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dideoxynucleotides halt DNA polymerization-->framents of various length-->electrophoresed to determine original sequence
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What are the main two types of Model Systems?
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Knock-Out = remove gene
Knock-In = insert a gene |
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Example of Codominance?
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blood groups
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What's up with Incomplete Penetrance?
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Not all individuals w/ mutant genotype have mutant phenotype
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What is Pleiotropy?
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1 gene has more than 1 effect on an individual's phenotype
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What is Imprinting?
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Differences in phenotype depend on if mutation is maternal or paternal origin
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What is Anticipation?
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Severity of the disease worsens or the age of onset is earlier in succeeding generations
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When do you see Loss of Heterozygosity?
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Tumor Suppressor Genes. When one mutant allele is inherited, the other allele must undergo a mutation in order to cause cancer (not so w/ oncogenes)
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What is a Dominant Negative Mutation?
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Exerts a Dominant Effect. The mutant product that prevents the normal product from functioning correctly
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What is Linkage Disequilibrium?
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When 2 different alleles at 2 linked loci occur together more often than expected by chance.
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What is Mosaicism?
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Occurs when different cells in the body have a different genetic make-up (e.g. lyonization)
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What is lyonization?
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random X inactivation seen in females
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What is Locus Heterogeneity?
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Mutations at different loci can produce the same phenotype (e.g. albinism)
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What is Heteroplasmy?
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When there is both normal and mutant mitochondrial DNA resulting in a variable expression of a mitochondrial inherited disease
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What is Uniparental Disomy?
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when the offspring receives 2 copies of a chromosome from 1 parent and no copies from the other
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If a population is in Hardy-Weinberg equilibrium, then what is the equation for Disease Prevalence?
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p^2 + 2pq + q^2 = 1
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If a population is in Hardy-Weinberg equilibrium, then what is the equation for Allele Prevalence?
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p + q = 1
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If a population is in Hardy-Weinberg equilibrium, then what is the equation for Heterozygote Prevalence?
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2pq = heterzygote prevalence
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If a population is in Hardy-Weinberg equilibrium, then what is the equation for prevalence of an x-linked recessive disease in males vs females?
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Males = q
Females = q^2 |
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What does Hardy-Weinberg laws assume?
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No mutation occurring at the locus
No selection for any of the genotypes at the locus Completely random mating No migration |
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What is up with an gene locus characterized by imprinting?
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Only 1 allele is active, the other is inactivated.
If a deletion of the active allele occurs, then you get disease |
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Main example of Imprinting?
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Prader-Willi/AngelMan's
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So what's going on w/ prader willi?
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Deletion of normally active Paternal Allele
MR, hyperphagia, obesity, hypogonadism, hypotonia |
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What's up with Angelman's Syndrome?
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Deletion of normally active Maternal allel
MR, seizures, ataxia, inappropriate laughter |
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Prader-Willi/Angelman's chromosome?
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15
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What is Hypophosphatemic Rickets?
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"vitamin D resistant rickets"
Inherited disorder-->Inc Phosphate wasting at proximal tubule-->rickets-like presentation |
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How does a mitochondrial inherited disease appear in a pedigree?
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Only transmitted through mom
All offspring of affected females may show signs of disease |
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Types of Mitochondrial Inherited diseases?
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Mito Myopathies (neuromuscular sx's)
Leber's Hereditary Optic Neuropathy (degeneration of retinal ganglion cells and axons-->acute loss of central vision |
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AUTOSOMAL DOMINANT DISEASES
Achondroplasia? |
Cell Signaling defect of fibroblast growth factor receptor 3.
Dwarfism: short limbs, normal head and trunk. Associated w/ advanced paternal age |
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AUTOSOMAL DOMINANT DISEASES
APKD? |
Adult Polycystic Kidney Disease
Always bilateral, multiple large cysts Present w/ flank pain, hematuria, HTN, progressive RF 90% due to mutant APKD1 (ch 16; 16 letters is polycystic kidney) Associated w/ polycystic liver, berry aneurysms, mitral valve prolapse IPKD is recessive |
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AUTOSOMAL DOMINANT DISEASES
familial adenomatous polyposis? |
After puberty, colon gets covered in polyps.
Progresses to colon cancer unless resected. Deletion of APC gene on Ch. 5 (polyp = 5 letters) |
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AUTOSOMAL DOMINANT DISEASES
familial hypercholesterolemia? |
Elevated LDL due to defective/absent LDL receptor
Heterozygous = 300mg/dL Homo's (rare) = 700mg/dL Severe atherosclerotic disease early in life (MI before 20) Tendon Xanthomas (achilles) |
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AUTOSOMAL DOMINANT DISEASES
hereditary hemorrhagic telangiectasia? |
Osler-Weber-Rendu Syndrome
Disorder of Blood Vessels Telangiectasias, recurrent epistaxis, skin discoloration, AV malformations |
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AUTOSOMAL DOMINANT DISEASES
hereditary spherocytosis? |
Spectrin or ankyrin defect-->spheroid RBC's-->hemolytic anemia
Inc MCHC Rx: splenectomy (curable) |
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AUTOSOMAL DOMINANT DISEASES
huntington's disease? |
Sx's: depression, progressive dementia, choreiform movements, caudate atrophy, dec GABA and ACH in brain
Onset between 20 and 50 Gene on Ch. 4; trinucleotide (CAG) repeat disorder |
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AUTOSOMAL DOMINANT DISEASES
marfan's? |
Fibrillin gene mutation-->CT disorer affecting skeleton, heart, and eyes.
Sx's: tall, long extremities, pectus excavatum, hyperextensive joints, long tapering fingers and toes, cystic medial necrosis of aorta-->incompetence and aortic dissections Floppy mitral valve Subluxation of lenses |
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AUTOSOMAL DOMINANT DISEASES
multiple endocrine neoplasias (MEN) |
Type I, II, and III
Tumors of pancreas, parathyroid, pituitary, thyroid, adrenal medulla Type II and III associated w/ ret gene |
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AUTOSOMAL DOMINANT DISEASES
Neurofibromatosis Type 1 |
Von Recklinghausen's Disease
Sx's: cafe-au-lait spots, neural tumors, Lisch nodules, skeletal disorders, optic pathway gliomas, pheochromocytoma Ch 17 (17 letters in von recklinghausen) |
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what is a lisch nodule?
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Pigmented Iris Hamartomas
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AUTOSOMAL DOMINANT DISEASES
Neurofibromatosis Type 2 |
Bilateral acoustic neuroma
Juvenile Cataracts NF2 gene on ch 22 |
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AUTOSOMAL DOMINANT DISEASES
tuberous sclerosis |
Sx's: facial lesions, hypopigmented ash leaf spots on skin, cortical and retinal hamartomas, seizures, MR, renal cysts and angiomyolipomas, cardiac rhabdomomas, Inc incidence of astrocytomas
Incomplete Penetrance Variable Presentation |
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AUTOSOMAL DOMINANT DISEASES
von hippel-lindau disease? |
Hemangioblastomas of retina/cerebellum/medulla
50% end up w/ multiple, bilateral renal cell carcinomas or other tumors Deletion of VHL gene (tumor suppressor) on Ch 3 |
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Examples of Auto Rec diseases?
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Albinism
IPKD CF Glycogen storage diseases PKU Sickle Cell Thalassemias |
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Inheritance and defect in Cystic Fibrosis?
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Auto Rec
Defect in CFTR gene on 7 |
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What does the CFTR gene normally do?
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Encodes CFTR Channel, which is responsible for secreting Cl in lung and GI tract AND reabsorbing Cl from sweat
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Defective CFTR gene--> ?
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Abnormally thick secretions plugging lungs, liver, pancreas-->recurrent pulm infections, pancreatic insufficiency, meconium ileus in neonates, infertility in men
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What is the most common lethal genetic disease in Caucasians?
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CF
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Dx for CF?
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Inc Cl in sweat test
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Rx for CF?
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N-acetylcysteine to loosen mucous plugs (cleaves disulfide bonds)
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X-linked Recessive Disorders (mnemonic)
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Be Wise, Fool's GOLD Heeds False Hope
Bruton's agammaglobulinemia Wiskott-Aldrich syndrome Fragile X G6PD def Ocular albinism Lesch-Nyhan Duchenne's (and becker's) MD Hemophilia a and b Fabry's disease Hunter's Syndrome |
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Muscular Dystrophies?
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Duchenne's
Becker's |
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Duchenne's Muscular Dystrophy
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X-linked, Frame-shift mutation-->deleted dystrophin gene-->accelerated muscle breakdown
Weakness starts in pelvis and moves up Pseudohypertrophy of calves Cardiac Myopathy Gower's maneuver to get up Onset before 5 |
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Kicker for Dystrophin Gene?
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longest known human gene = inc rate of spontaneous mutations
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Becker's MD?
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X-linked mutated dystrophin gene-->less severe
Onset in adolescence or early adulthood |
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Dx of MD?
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Inc CPK and a Muscle Biopsy
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What's up with Fragile X Sydrome?
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X-linked defect of methylation and expression of FMR1 gene--> chromosomal breakage
Trinucleotide (CGG) repeat disorder Sx's: macro-orchidism (big testes), long face w/ large jaw, large everted ears, autism |
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What are the two most common causes of genetic MR?
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1. down's
2. Fragile X |
