Exam 4 Diseases

Question 1

ataxia telangiectasia

Answer 1

rare inherited disorder due to mutation in gene for kinase ATM
ataxia - difficulty coordinating movement
telangiectasia - appearance of small, widened blood vessels on skin
Patients are susceptible to infections and are at increased risk of leukemias and lymphomas. Highly sensitive to radiation exposure such as x-rays

Question 2

burkitts Lymphoma

Answer 2

Translocation move cMyc gene from normal position on chromosome 8 to chromosome 14. New position is new control elements for antibody heavy chain. high levels of cMyc in B-cells –> B-cells become cancerous

Question 3

Retinoblastoma

Answer 3

mutation in gene for Rb = RB1
Rb inhibits cells cell progression when underphosphorylated.
INHERITED FORM - more common - one mutant allele from parent and somatic mutation in second allele = cant sequester E2F which is a transcription factor that promotes growth = cancer.Tumors in infancy and are bilateral.
SPORADIC FORM– less common - both copies of RB1 are mutated. Same effect but this is rarely bilateral.

Question 4

Li-Fraumeni Syndrome

Answer 4

heritable condition conferring increased susceptibility to many forms of cancer due to mutant TP53 allele - Dominant negative effect disables P53 tetramer function. Cells w/ damaged DNA continue to divide. Dominant heritance. early occurence of multiple tumors. Multiple affected family members.

Question 5

HPV-induced cervical cancer

Answer 5

HPV produced E6 (binds p53 and targets it for destruction) and E7 (binds and degrades Rb which displaces E2F).

Question 6

Neurofibromatosis-1 (NF1)

Answer 6

loss of function of NF1 gene - encodes neurofibromin. Neurofibromin is protein that promotes GTPase activity of Ras - shuts off Ras. Without it Ras is on for longer. Formation of “cafe au lait” spots which a remultiple non-malignant peripheral nerve tumors (neurofibromes) iris Lisch nodudles.

Question 7

Hereditary colon cancers (FAP)

Answer 7

100-1000s of colorectal polyps in pt - 100% chance to dev into colorectal adenocarcinoma. mutations in APC - tumor suppressor helps down regulate WNT pathway and B-catenin which signal for growth and proliferation. APC forms destruction complex with B-Catenin. If not degraded B-catenin enters nucleus and triggers transcription - constant stimulation by cyclin D and c-Myc. Pt inherits one defective gene and other allele mutates on own. Additional mutations occur via oncogenic forms of Ras and p53. APC also checks for kinetochore and microtubule attachment so if not present = genome instability and aneuploidy.

Question 8

Hereditary nonpolyposis colorectal carcinoma (HNPCC - Lync Syndrome)

Answer 8

defective DNA mismatch repair - MSH2=identifies mismatches. MLH1 = participates in repair process. First allele mutated from parent and second allele lost yields lots of mutations fast. Typically microsatelite regions - usually in noncoding areas and silent but may be in coding or control region= protein function impacted (ex: BAX function altered and supression of apoptosis)
Lost of mismatch repair capacity precipitates adenoma formation = more mutations = carcinomas and metastasis

strand directed mismatch repair - disease may arise bc strand directed mismatch repair is not functioning.

Question 9

Chronic Myelogenous Leukemina

Answer 9

translocation b/w chromosomes 9 & 12 = Philadelphia chromosome. Fuses BCR and ABL genes together. BCR is unk but ABL encodes soluble protein kinase. Targets many tissues but especially common in bone marrow = Chronic myeloid leukemia (CML) Imatinib mesylate - specific inhibitor of BCR-ABL kinase activity.

Question 10

streptomycin

Answer 10

binds small subunit and inhibits initiation. Causes mistranslation of codons

Question 11

neomycin/gentamicin

Answer 11

causes mistranslation of codons

Question 12

tetracycline

Answer 12

blocks A-site and prevents tRNA binding

Question 13

chloramphenicol

Answer 13

prevents peptidyl bond formation

Question 14

ricin

Answer 14

ribosome inactivator found in castor beans. Removes RNA from ribosome and deglycosylation –> ribosome cants recognize incoming tRNA (loss of catalytic function). Messes with one ribosome and moves onto the next rib

Question 15

diphtheria toxin

Answer 15

ribosyltransferase secreted by some bacteria. inactivates EF2 by transfering ADP ribose to it from NAD+. Interferes with elongation which leaves the task half finished - worse than just not beginning the task.

Question 16

congenital disorder of glycosylation I (CDG I)

Answer 16

defective synthesis of lipid linked oligosaccharide precursor - 12 variants – basically issue making sugar tree in ER. gel for size

Question 17

congenital disorder of glycosylation II (CDG II)

Answer 17

defective trimming of oligosaccharide chain - 6 variants - happens in Golgi. gell for size and charge: affects most of our functional proteins

Question 18

cystic fibrosis

Answer 18

protein sorting disease - deletion impairs trafficking of CFTR1 protein to cell surface. Protein is not properly glycosylated. Protein is moved into cytosol and degraded

Question 19

I-cell disease

Answer 19

protein sorting disease - surface mannose residues are not phosphorylated. lysosomal proteins do not reach correct compartment and appear in serum. lysosomal degredation of proteins and carbs is impaired. fibroblasts appear dense bc of inclusion bodies - granules and lysosomal proteins in the cytosol.

Question 20

alpha amanitin –>amanita phalloides poisoning

Answer 20

RNA Pol II inhibitor found in wild mushrooms which prevents liver from making essential proteins = nausea, coma, and death due to hepatic encaphalopathy. Brain swells due to urea build up.

Question 21

rafamipicin

Answer 21

potent inhibitor of prokaryotic RNA Pol II but isn’t reactive with human RNA Pol II. Treats myobacterial infections: TB and leprosy

Question 22

beta-thalessemia

Answer 22

mutation in beta-globin gene at first intron/exon boundary disrupts splicing = non-functional protein = reduced synthesis = less hemoglobin = anemia

Question 23

PKU

Answer 23

inability to convert Phe into Tyr due to lack of Phenalalanine Hydroxylase activity. Enzyme has a mutation at a particular 5’ splice donor site in gene. results in defective splicing and protein products is missing a needed exon = degredation. Symptoms = microcephaly, intellectual disability, and facial anomalies

Question 24

Rubinstein-Taybi

Answer 24

Point mutation in CRB-EP300 complex protein that functions as a HAT to relax chromatin during PKA mediated transcriptional control.
(PKA phosphorylates CREB which binds to CRE. CRE is in promoter region and recruits CREB binding protein which recruits and binds EP300 to function as a HAT and relax chromatin for transcription)

Question 25

Tamoxifen

Answer 25

competitive inhibitor for estrogen receptors. Estrogen receptors trigger proliferation of breast cancer cells. Tamoxifen can bind the DNA receptor but prevents the bind of other transcription factors needed for transcription and cell proliferation.

Question 26

Xeroderma pigmentosum

Answer 26

extreme sensitivity to sunlight due to mutations that prevent nucleotide excision repair (of thymine dimers). Results in pigmentation changes and skin cancers.

Question 27

Inhibitors of DNA replication (3)

Answer 27

1) cytarabine- analogue of cytidine - has arabinose sugar instead of ribose. converted to cytarabine triphosphate and competes with ribonuclease - if incorporated = DNA damage and triggers cell death. 2) cyclophosphamide- PRODRUG - converted to phosphoramide mustard by liver. bifunctional: forms interand intra strand DNA crosslinks which blocks replication and triggers cell death 3) doxorubicin- forms tripartite complex with DNA and topoisomerase II. Topoisomerase makes double strand break and doxorubicin prevents ligation bc doxo gets in the way. Beraks accumulate = apoptosis

Question 28

nalidixic acid target:

Answer 28

bacterial topoisomerase II (antibacterial drug)

Question 29

ciproflaxacin target:

Answer 29

bacterial topoisomerase II (antibacterial drug)

Question 30

doxorubicin target:

Answer 30

human topoisomerase II (anticancer drug)

Question 31

proline modification:

Answer 31

can be hydroxylated to function in the collagen triple helix - failure = collagen disorders ie Scurvy

Question 32

lysine modification:

Answer 32

acetylated to change overall charge of histones (HATS) - issues lead to global changes in gene expression

Question 33

cysteine modification:

Answer 33

tiol group converted into aldehyde to form C-alpha-formylglycine. Used in lysosomal sulfatases - issues result in accumulation of sulfated glycosaminoglycans in lysosomes

Question 34

addition of hydrophobic moieties to proteins:

Answer 34

adding myristic acid to N-term of glycine adding palmitic acid to selected cysteine residues adding isoprenoids to cysteine near c-terminus adding GPI-anchor to tether to external side of the membrane.