Unit+1+Diseases+and+Drugs


 * **[|Gout]** – purine precipitate accumulates in joints
 * Nonpolyposis Colorectal Cancer - problems with Mismatch repair
 * **TF II H** – problems with Nucleotide Excision Repair
 * **[|Xeroderma pigmentosum]** - light sensitivity, abnormal pigmentation, cancer susceptibility, neuorological abnormalities, unscheduled DNA synthesis
 * **[|Cockayne syndrome]**
 * **[|Trichothiodystrophy]**
 * Splicing Defects
 * **[|Marfan syndrome]** : caused by mutations that disrupt splicing of the fibrillin gene transcript (fibrillin is a connective tissue protein that is important for the integrity of the walls of the heart and blood vessels). They are tall and prone to aneurysms.
 * Mutations in DNA Control Elements
 * **[|Beta-thalassemia]** (from thalassa, Greek for sea): mild inherited anemia (low hemoglobin count). Caused, here, by a mutation in the promoter of the b-globin gene, resulting in lowered rate of production of b-globin protein. (less promotion = less transcription) – associated with problems in the TATA box
 * **Gamma-delta-beta thalassemia**: more serious anemia caused by a deletion in the locus control region for the transcription of all globin genes, resulting in the loss of globin transcription.
 * **Hemophilia B Leyden**: X-linked disease (usually males) that affects clotting. Again, a problem in the promoter region of a clotting protein gene. Tends to get partially better at puberty.
 * **[|Fragile-X syndrome]** : Again, usually a disease of men. Results in mental retardation and atypical development of the face with enlarged testicles (macroorchidism). Caused by an expansion in the CGG count upstream of a particular gene (the FMR1 gene), which results in an abnormally high rate of methylation in that region and transcriptional silencing of the gene.
 * Mutations in SSDBP’s
 * **[|Craniosynostosis]** : premature closure of the skull sutures in infants. Arises from a mutation in a homeodomain protein that causes the protein to bind more strongly, creating a "hypermorphic allele" that activates genes more strongly than it should. (upregulates proteins that close sutures via homeodomain mutation)
 * **[|Waardenburg Syndrome]** **Type II** – white streak of hair, wide face. 15% of cases result from mutation in MITF gene (encodes a bHLH (basic Helix-loop-helix) DNA binding protein), affects transcription of genes important for pigmentation and hearing
 * Waardenburg syndrome: deafness, pigmentation defects. Associated with mutations in the MITF (microphthalmia-associated transcription factor) gene (which codes for a bHLH binding protein that regulates melanocyte development).
 * **[|Androgen insensitivity syndrome]** : Feminization or undermasculinization. Indifference of androgen receptors to androgen hormones. Caused by a mutation in the zinc-finger androgen receptor binding domain or ligand binding domain. This downregulates the transcription of genes controlled by male androgens.
 * Diseases associated with **HAT’s** and **HDAC’s**
 * **[|Leukemia]** : haematopoietic (formation of blood cell components) disease involving chromosomal translocations over-activating fusion proteins that alter the activity of HATs or HDACs.
 * **[|Rubinstein-Taybi syndrome]** : growth and mental retardation, broad thumbs and toes, craniofacial dysmorphism. Results from mutations in one copy of **CREB binding protein** gene (haploinsufficiency); CBP is a widespread HAT important in development and its insufficiency has particularly drastic effects.
 * Certain viruses (rhinovirus, poliovirus, etc) prevent **eIF-4E** and **eIF-4G** from coming together and forming the initiator complex.
 * Instead of participating in cap-dependant translation, ribosomes are free to bind to areas of the viral 5' UTR called Internal Ribosomal Entry Sites (**IRESes**) (as well as any host IRESes present). Thus predominantly the viral mRNA will be translated instead of the host mRNA.
 * Post-Translational Modification
 * **[|Scurvy]** - Hydroxylation of proline residues in collagen stabilizes the structures, mediated by vitamin C. Underhydroxylation of collagen proline residues results in weak connective tissue.
 * **Clotting Disorders** – Carboxylation of glutamate residues on prothrombin important for proper clotting. This process is mediated by Vit. K, thus Vit K deficiency à clotting disorder. **[|Warfarin]** is an anticlotting drug that targets carboxylation of prothrombin
 * **[|Congenital Disorder of Glycosylation]** (CDG) – cells need to glycosylate asparagine residues of proteins within cell membrane to increase their hydrophilicity. Dysfunction of glycosylation mechanism results in CDG
 * Protein Folding Defects
 * **[|Prion disease]** - the same prion protein simply misfolded, which then causes other normal prion proteins to misfold. These are altered from alpha helices to beta sheets causing them to aggregate within amyloid plaques leading to neuron loss and gliosis
 * **[|Alzheimer’s Disease]** : the normal AB-40 folds correctly, however the slightly different AB-42 misfolds and aggregates into amyloid plaques. This leads to B-amyloid plaque and tau tangles.
 * **[|Parkinson’s Disease]** : Beta-synuclein misfolds into Lewy Bodies.
 * **[|Amyloidosis]** : Generalized protein misfolding in the rest of the body leading to a variety of disease (from Type II diabetes to Cardiac amyloidosis).
 * Antibiotics
 * **[|alpha-amanitin]** : extremely toxic substance found in death cap mushrooms. Acts by inhibiting the movement of RNA Pol II, binding its bridge substructure so that translocation of the polymerase down the DNA chain can't happen.
 * **[|rifampicin]** : broad-spectrum antibiotic. Acts by binding the beta subunit of bacterial RNA polymerase, plugging up the exit chamber where assembled RNA exits the transcriptional complex. Thus elongation is prevented from going farther than a few base pairs due to having nowhere to go.
 * **[|Tamoxifen]** acts as an antagonist to estrogen, binding to the estrogen receptors as a ligand without providing dimerization-- thus effectively preventing estrogen from binding to its site of action and preventing the transcriptional effect of estrogen receptors.
 * Antibiotics inhibit translation by interfering with the ribosome (both 30S and 50S subunits) through tRNA binding, elongation and peptidyl transferase.
 * **[|Rapamycin]** (cancer drug) phosphorylates 4E-BP so that the initiation complex cannot be formed, downregulating translation.
 * **[|Gleevec]** is a cancer treatment that competitively inhibits **bcr-abl** kinase such that the substrate is not phosphorylated and active and the tumor cell cannot proliferate via an abberant bcr-able gene.
 * **[|Velcade]** inhibits a proteosome that degrades good proteins resulting in multiple myeloma