BS Hard-to-Remember updated 6/9 Arrow = SMOOTH ER (SER) = network of membranous sacs, vesicles + tubules continuous with the RER

but lacking ribosomes * enzymes involved in biosynthesis of phospholipids, TGs, sterols (e.g. steroid hormones) ABUNDANT IN CORPUS LUTEUM active synthesizers female sex hormones ADRENALS (steroid hormone synth) *detox rxns (glycogen degredation, gluconeogenesis, lipoprotein particle assembly) lots in liver MT: 9 doublets + 2 (ciliary axoneme) +2 dynein arms) RER ("parallel arrays of membraneBound cisternae populated with multiple electron-dense dots Cell undergoing mitosis (HETEROCHROMATIN condensed, tightly wrapped around histones vs. loosely-packed transcriptionally active euchromatin)

1. Gene X is on opposite strand sequence will run in opposite direction 2. start codon ATP7B is "near first exon gene X" 5'UTR region ATP7B gene is thus either immediately upstream of its translation start codon or immediately downstream gene X exon 1 st opposite Gene X 1 intron (see below) Different receptor types ARTERIOLlongitudinal x-section A= endothelial cell intima B = PMN in vessel C = basal lamina underlying endothelium D = arteriolar adventitia E = smooth muscle cell in media (b/c this section is longitudinal, the normally "fusiform, spindleshaped" SM cell appears round BUT STILL SHOULD ID THIS EASILY given it's LOCATION b/w ADVENTITIA + INTIMA (e.g. thus = media)

DO GEL READINGS QUICKLY if given a gel and asked for the complementary sequence look at the TOP (which is negative side + therefore the end part of the given gene but we want complementary so this will be start of that) + then just switch to complementary NT (eg AT) only do for as much as needed to find answer in choices immediately look at the last NT in sequence = G Complementary will start with opposite of this = C so know strand starts C, T (vs. G, A)

MISSENSE mutation = MC MUTATION TYPE Large segment deletion alpha thalassemia

BIOCHEM
Chronic arthritis, black urine Alkaptonuria Liver and kidney dz 2/2 AA issue Albinism Pale hair + skin, MR, musty smell Tyrosine

Tyrosinosis Tyrosine def. melanin Pale hair + r/o melanoma/skin ca Phenylketonuria (AR) Phenyalaninetyrisone deficient (phenyl enzyme or TB4 coenzyme)

Branched AAs

Isoleucine Leucine Valine Maple syrup urine dz CNS, MR, death, sugar-smell diaper) *"I Love Vermont maple syrup" Homocysteinuria methionine/cysteine (cysteine becomes essential AA) Inherited HEMOLYTIC anemia = 1. G6PD deficiency or 2. PK deficiency If woman, unless information given to suggest x-linked (and then receiving 2 bad xs), most likely pyruvate kinase since this is not sexlinked (AR) NO Heinz (these are in G6PD RBC denaturation) RIGHT SHIFT in oxygenation curve if PK, then glycolytic intermediates back up alternate pathway includes 2,3 BPG affinity for O2 (more offloading, LESS pickup - (REMEMBER, fetal Hgb, HbF has 2,3BPG to allow for affinity/more pickup from mom) AD

MR, osteoporosis, marfinoid-habitus, lens subluxation What RBC changes would you expect in a female who presents with an inherited hemolytic anemia

Heritability familial hypercholesterolemia

MOLECULAR + CELL BIO

RER secretory/exported proteins protein folding here N-linked oligosacch addition Nissl bodies in neurons ChAT enzyme that makes Ach; peptide NTs GI goblet cells (mucous secretion), plasma cells (Ab-secretion)

Chaperones

Class of specialized proteins that function to assist proper folding newly synthesized proteins (properGolgiplasma mem etc.) If they are dysfunctional + poor folding protein is polyubiquinated lysosome for degredation Will detect protein IN RER BUT WON'T find receptor (the protein) on membrane (e.g. all is good until RER) Ex calnexin, calreticulin STEROID synth DETOX rx, poison hepatocytes (detox) + adrenal ctx (produces steroid hormones) Proteins/lipids ERplasma membrane + vesicles Modifies N-oligos on nitrogen of asparagine Adds O-oligos on serine + threonine Add MANNOSE-6-phos for traffic to lysosomes o FYI : I-CELL DISEASE don't tag with mannose secrete enzymes OUTSIDE cell instead of lysosome Coarse face, clouded corneas, restricted jts, plasma lysosomal enzymes Fatal in chldhood

SER

Golgi

COPI

retrograde, GolgiER

COPII Endosome Clathrin

anterograde, RERcis-Golgi outside or Golgi lysosome or Golgi Trans-Golgi lysosomes, Plasma membrane endosomes R-mediated endocytosis (forms coat) membrane-enclosed organelle for catabolism very LCFAs + AAs Proteins destined for peroxisome incorporation synthesized on free polysomes (ribosomes?)

Peroxisome

Proteosome Microtubule general action, processes

= degradation damaged/unnecessary proteins tagged by UBIQUITIN Cilia (details below), flagella Mitotic spindle Axonal trafficking Centrioles *arranged with neg ( - ) end near centrosome (MTOC) + pos (+) radiates OUT Alpha + B-tubulin dimers, each with 2 GTP DYNEIN = RETROGRADE (+ -) e.g. toward NUCLEUS = NEGATIVE (hannahs home-made mnemonics "I'm DYNING IN tonight" (coming to the home/nucleus) **CLINICAL CORRELATE herpes, polio, rabies viruses + tetanus toxin are all exogenous substances that affect neuron cell bodies via RETROGRADE axonal transport (Im "DYing over here", regressing retrograde") KINESIN = ANTEROGRADE ( - +) e.g. away from nucleus

Microtubules - dynein vs. kinesin

Tubulin Disease caused by defect in microtubule polymerization and fusion of phagosome with lysosome

Monomeric unites that comprise MT (necessary for movement cargo within cell) Chediak-Hagashi MT polmerization defect fusion phagosomes+lysosomes Recurrent pyogenic infection Partial albino Peripheral neuropathy

Cilia structure Disease caused by immotile cilia (and cause of immotility)

9+2 MT arrangement Axonal dynein-ATPase links peripheral 9 dblts cilium bending KARTAGENERS immotile cilia d/t dynein arm defect Male/female infertility Bronchiectasis Recurrent sinusitis Situs inversus Retrograde axonal transport dysf Mebendazole/thiabendazole anti-helminth Griseofulvin anti-fungal Vincristine, Vinblastine anti-CA Paclitaxel anti-breast CA Colchicine anti-gout

Drugs acting on microtubules to treat fungus? To treat worms? To treat cancer (2)? To treat gout?

Actin/Myosin general actions

*Microvilli Muscle ctx Cytokinesis Adherens junctions d/t F508 mutation (deletion phenylalanine) interference folding + post-translational processing of oligosaccharide side chiains degraded by proteosome instead of membrane translocation

Location where processing "goes wrong" in cystic fibrosis

CFTR protein is misfolded in endoplasmic reticulum

DNA ligase

Catalyzes formation phosphodiester bond b/w 3' OH of DNA fragment with adjacent DNA 5'-monophosphate grp

DNA Polymerase I

Read 3' 5' (e.g. start at OH grp and read toward phos grp) Synth 5'3' (adding new NT's phospho grp on to the free OH grp of growing strand "hydroxyl attack" + energy from new NTs phos grp) Both polymerization NTs and processing/repair mechs Prokaryote only Part of multiprotein complex, major replicating enzyme e. coli swivel points in DNA to relieve strain at replication (cut+reseal DNA) Quinolones interfere here

Polymerase III Topoisomerase and Abx Cytosine deamination Dolichol

= URACIL if intact DNA repair mechanisms, these will be repaired (mismatch repair genes will eliminate via base excision) Substrate for forming branched "carbohydrate trees" that are transferred to proteins in synthesis glycoproteins (mostly protein w/ some attached sugars) on RER goes to golgi, then either plasma membrane/lysosome/secreted protein

"scientist wants to characterize the carbohydrate chains that will be transferred to protein component of albumin. Which molecule functions for synthesis of these chains? *N-linked carbohydrate chains that will be transferred to protein component of albumin are assembled in RER + attached to colichol phosphate transferred to nitrogen of asparagine to form glycoproeins Arachidonic acid Ceramide secreted = albumin retained in membrane = insulin-R targeted to lysosome = hexosaminidase A (tay-sachs)

Precursor of: PGs Thromboxanes Leukotrienes

FA in phospholipid membrane released by phospholipase A2 Parent sphingolipid from which sphingomyelin, cerebrosides, gangliosides are derived (think LYSOSOMAL STORAGE DISORDERS e.g. niemann-pick genetic deficiencies of lysosomal enzymes that should digest these spingolipids cause the diseases) GAG (glycosaminoglycan) -precursor of proteoglycan (carbs w/ small proteins remember if protein>>carb component = glycoprotein) - part of ECM Types: chondroitin sulfate, hyaluronic acid Remember *dermatan + heparan sulfates are substrates to enzymes deficient in HURLER (Worse, corneal cloud) + HUNTER dz Binds ribosomal 30s subunit (prokaryotic small subunit euk = 40s) prevents aminoacyl-tRNA attachment Streptomycin, gentamycin, tobramycin, amikacin Inhibits eIFs = elongating initiation factors that help assemble 30s ribosomal subunit with initiatior tRNA

Dermatan sulfate

Tetracycline Aminoglycoside

Ribosome formation, translation

30+50s = 70s prok 40+60=80s euyk ATP activates tRNA (A=activatation) GTP = initiation, translocation, holding on to tRNA (G=gripping, going places) A site incoming aminoacyl-tRNA P growing polypeptide chain E = empty tRNA AA has been transferred to growing molecule on P site (exit) Ribosome advances 3 NTs toward 3' end mRNA (e.g. toward end whose last NT has free OH) This moves peptidyl RNA to P site = translocation

Chloramphenicol

2 MOAs at 50S ribosome 1. 2. Inihibits 50S peptidyltransferase (this is the "top part" ribosome complex Blocks peptide bond formation (so does clinda)

RIBOZYME

RNA molecule that has catalyst (E.g. enzymatic "yme") activity Ribosomal rRNA catalyzes peptide bond formation, transfers growing polypeptide to AA in A site (which then moves to P site when ribosome moves 3NTs forward) Catalyzes sequence-specific cleavage RNA PDE bonds d/t 2 structure they form (looks like head of hammer) - possible use as treatment of "activating" mutated genes (e.g. SOD1 in ALS) synthetic hammerhead RNA w/ complementary sequence to mutant SOD1 mRNA could potentially bind specifically to mutant + destroy via catalyzing PDE bond cleavage "removes mRNA without direct inhibition of translation initiation" it's a destruction rather than inhibition Erythromycin, azithromycin, clarithro static (Vs. cidal) 50S inhibitor blocks translocation this uses GTP normally *(CHLORAMPHENICOL is also acting at 50S but blocking PEPTIDYLtransferase)

Hammerhead Ribozyme

Macrolides

Clindamycin "Buy AT 30, CCELL (sell) at 50"

Same as second MOA chloramphenicol block peptide bond formation at 50S ribosome 30S Aminoglycosides (Strepto, genta, tobra) bacteriocidal Tetracycline bacteriostatic 50S Chloramphenicol, Clindamycin static Erythromycin (macrolide) static Lincomycin static Linezolid (variable static vs. cidal) **Linezolid is for VREs

Mutation in early post-translational modification collagen DNA methylation associated dz

Ehler-Danlos skin + msk abnormalities Fragile X This in addition to TRI-NT repeat EXPANSION CGG triNT repeat in FMRI gene r/o CHROMOSOMAL BREAK nd st 2 MCC MR (1 = Downs) MACROCHORDISM (big testes), long face, LARGE + everted ears, autism, MVP* (Fragile X = Xtra larges teses/jaws/ears)

Thick gums, large tongue, hip dislocation, clubbing feet, relative immobility extremities and abnormal inclusions in fibroblasts

I-CELL dz Def. N-acetylglucosamine-1-phosptransferase = defect in addition mannose-6phosphate moiety to lysosomal enzymes released to extracellar space so culture medium will contain lysosomal enzyme activity - Coarse facies, skeletal abnll, psychomotor retardation - Type 1 complete def., death in childhood - Type 3 partial deficiency = milder dz (pseudo-Hurler) survives to adulthood

Incorrect splicing introns associated with what hematologic disorder

B-THALASSEMIA B-globin gene (chr 11, HBB gene) incorrectly spliced to give B- or Bo (small function)

Hematologic dz caused by missense pt mutation

HbS Sickle cell Change A-->T at position 6 allows glutaminevaline HbC = modified version this error (glutaminelysine) less serious and Asx if HbC/A but heterozygous HbS/C can act like HbSS and homozygote HbCC gives hemolytic anemia

Transition vs. transversion pt mutation

Transition is substitution within same "class" purinepurine / pyrpyr (same ring "type") Transversion = switch b/w purine/pyr (A-T T-A or C-G) (remember Purine PURe As Gold = Glutamine, adenosine; pyrimidine CUT the PY = cytosine, thymidine, uracil in proks)

Tautomerism switch point mutation

Switch single vs. double bond via migration H+

Tautomers are isomers (structural isomers) of organic compounds that readily interconvert by a chemical reaction called tautomerization.[1][2]This reaction commonly results in the formal migration of a hydrogenatom or proton, accompanied by a switch of a single bond and adjacentdouble bond. The concept of tautomerizations is called tautomerism.Because of the rapid interconversion, tautomers are generally considered to be the same chemical compound. Tautomerism is a special case of structural isomerism and can play an important role in non-canonical base pairing in DNA and especially RNA molecules.

Significance of cytosine deamination

CU this is the only deamination rxn that can be CORRECTED via uracil-DNA glycosylase (this can be missed in mismatch repair HNPCC, endometrial CA) *STEPS REPAIR: 1.Uracil-DNA glycosylase generates Abasic site = AP 2. DNA AP endonuclease sees newly formed Abasic site breaks PDE bond 3. DNA Polymerase sees break and creates nick + fills 4. DNA Ligase reforms seal with PDE bond ALSO CAN RECOGNIZE related deaminase rxn of METHYLATED cytosine (methylated in regulation gene transcription epigenetics) o 5methylcytosinethymine + ammonia (MC single NT mutation) corrected via thymine-DNA glycosylase fixes cystinethymine pt mutation in daughter cell o **Remember, thymine is a methylated uracil so it makes sense that CU would have methyl-CT all others NOT recognized o Adeninehypoxanthine (this now prefers cytosine instead of thymidine) o Guaninexanthine (this now prefers thymidine instead of cytosine)

*recall deamination = removal of amino grp from molecule NT base with ketone NT base with methyl grp Alkylating agents Guanine Thymine Cross-link guanine NTs in DNA damaging it enough to stop division Cisplatin Carboplatin

Base analog agents

Incorrectly incorporate the analog into DNA but chemically different enough to not make targeted protein, e.g. mismatch at base-pairing causes daughter DNA mutated BrdU find replicating cells for research

Methylating agents

Transfer methyl grps to DNA NT bases (not used for cancer Rx since it doesn't lead to cell death) *MGMT = methylguanine methyltransferase repairs EMS = ethyl methanesulfonate guanine alkylation that can induce high rates of mutations used in genetic screens/assays to induce mutations to be studied

Antimetabolite

5-FU (fluorouracil) pyrimidine analog; "suicide inhibitor" irreversible inhibition thymidylate synthase Antipurine azathioprine (cleaved to 6-MP), thioguanine Antifolate MTX (analogue that binds, inhibiting DHFR and formation THF), TMP, pyrimethamine, pemetrexed

DNA intercalating agent

Insert b/w 2 NT pairs DNA transcription/replication Fluorescent dye Ethidium Bromide Cancer Rx Doxorubicin, Daunorubicin Aflatoxin = Aspergillis Thalidomide teratogen with strict use policy for last resort anti-inflammatory (leprosy) + salvage chemo in MM (With dexamethosone) Birth defect = PHOCOMELIA (horrible limb deformities as well as other body regions)

DNA cross-linking agents

Form covalent bond b/w DNA NT bases can't replicate/transcribe Platinum

Free radicals

Highly active in presence of unpaired electrons Age-related cell damage Superoxide H2O2 Hydroxyl radicals

Ionizing mutagens + UV

UV = wavelenth/energy vs. normal length covalent adjacent thymine bond formed THYMINE DIMER (r/o skin ca) Ionizing radiation radioactive materials with high energy that REMOVE electron from molecule/atom damage/death

Mutagens requiring repair via base excision

Xrays O2 radicals Alkylating agents Spontaneous rxns

uracil abasic sites created (AP sites) or single strand break (MCC = CU deamination) DNA glycosylase + AP endonuclease remove/repaire, polymerase+ligase fill in Errors of replication A-G mismatch T-C mismatch Insertion Deletion Mismatch repair (hMSH/hMLH)

Recombinational repair

One damaged strand has some replication use as template Nonhmologous end-joining (ALWAYS MUTAGENIC) DNA ligase complexes join separate ends dbl helix Sequence = "signal recognition particle" (SNP) attaches growing peptide + ribosomal complex to RER opens up channel allowing peptide to thread into ER lumen Will be on any protein destined to be secreted / membrane-bound / lysosomal If absent protein would be UNABLE TO enter RER in first place (pre-folding error) Contain enzymes (made in RER) that degrade sugars (glycosidases) + proteins (proteases) Connective tissue Muscle *note connects cytoplasmic bodies to membrane dense plaques in actin filament structure of smooth muscle; cardiac + skeletal myopathies associated w/ mutations in this protein Epithelial cells neuroGLIAL cells astrocytoma, ependymal cells **REMEMBER GFAP only marks astrocytomas, for prognosis use Ki-67 Neurons Mebendazole/thiabendazole anti-helminth Griseofulvin anti-fungal Vincristine, Vinblastine anti-CA Paclitaxel anti-breast CA Colchicine anti-gout KARTAGENERS immotile cilia d/t dynein arm defect Male/female infertility Bronchiectasis Recurrent sinusitis Situs inversus

N-terminal hydrophobic signal sequence added on during synthesis via cytoplasmic ribosomes

Lysosomes Intermediate filament stains vimentin Intermediate filament stains desmin

Intermediate filament stains cytokeratin Intermediate filament stains GFAP Intermediate filament stains neurofilaments Drugs that act on microtubules

Dynein arm defects

Partial albinism, peripheral neuropathy and recurrent pyogenic infections 2/2 molecular bio issue

Chediak-Hagashi MT polmerization defect fusion phagosomes+lysosomes Recurrent pyogenic inection Partial albino Peripheral neuropathy

Kinesin vs. Dynein

DYNEIN = RETROGRADE (+ -) e.g. toward nucleus KINESIN = ANTEROGRADE ( - +) e.g. away from nucleus

Make-up of microvilli Actin, myosin, MT roles in replication Plasma membrane composition leading to decreased fluidity and higher melting temp RER activity + what cells have more

actin/myosin NOT microtubules Actin/myosin = cytokinesis Microtubules = mitotic spindle, centrioles MORE cholesteroal and/or MORE long saturated FAs secretory/exported proteins N-linked oligosacch addition Nissl bodies in neurons ChAT enzyme that makes Ach; peptide NTs GI goblet cells (mucous secretion), plasma cells (Ab-secretion) STEROID synth DETOX rx, poison hepatocytes (detox) + adrenal ctx (produces steroid hormones)

SER activity + what cells

Mitosis order

Interphase Prophase Metaphase Anaphase Telophase "PMAT" or "People Meet And Talk" Hand action mnemonic Prophase = fingers linked together in the middle Metaphase = MIDDLE (flat hands) Anaphase = pulled APART (hands apart) Telophase = TWO (close fingers to two fists)

Sign and significance of tripolar mitoses

= 3 clusters of chromosomes seen on telophase Signifies malignancy in tumor

2 drugs that act on Na/K ATPase channel directly (not neuro)

Ouabain binds K+ site Digoxin/digitoxin (glycosides) direct inhibit Na/K = indirect inhib Na/Ca (true target) [Ca2+]in = contract Phosphorylated = ACTIVE ATPADP (donates phos) "Be (So Totally) Cool, Read Books I = Bone, Skin, tendon Type ONE = BONE Type TWO = carTWOlage Type III = ThreE D defective in Ehlers-Danlos "Four = Under the Floor" II = cartilage (with hyaline), vitreous body + nucleus pulposus III = Reticulin = skin, vessels, uterus, fetal tissue, granulation tissue IV = Basement membrane (Easy, think goodpastures)

Na/K pump activation Collagen types I IV

Disease a/w DEFECT in Type 1 collagen

Osteogenesis imperfecta ("BRITTLE BONE") COL1A1/2 The one that looks like child abuse Multiple fx w/ minimal trauma BLUE SCLERA (translucent CT over choroid) Hearing loss (ABNL MIDDLE EAR BONE) DENTAL lack dentin

*remember I = Bone, Skin, tendon Type ONE = BONE

10

Disease a/w DEFECT in Type 3 collagen

Ehlers-Danlos COL3A1 collagen + lysine hydroxylase gene mutations Hyperextensible skin Easy BRUISING/Bleeds Hypermobile jts TYPE 4 (rare) = MENKE's dz (x-linked depigmented, lusterless KINKY hair with many facial/ocular/vascular/cerebral manigestations, copper transport defect and activity copper-depndent enzymes LYSYL OXIDASE REMEMBER, THIS IS CU-DEPENDENT ENZYME that crosslinks pre-collagein in ECM to form mature collagen) +/- associated with: Joint dislocation BERRY ANEURYSM Organ rupture

**6 types w/ varying inheritance/severity (AD or AR)

*remember III = Reticulin = skin, vessels, uterus, fetal tissue, granulation tissue Disease a/w DEFECT in Type 4 collagen Type III = ThreE D defective in Ehlers-Danlos

Alport Syndrome (goodpasture = autoimmune not defect) hereditary GN ESRD HEARING LOSS +/- ocular disturbances MC type = X-LINKED RECESSIVE (BOYS)

*remember IV = Basement membrane (Easy, think goodpastures) Collagen 4 steps within fibroblasts + location 1. Synthesis (RER) o Translate alpha chains = PRE-PRO-collagen o Gly-X-Y X/Y = PROLINE, hydroxyproline/LYSINE Hydroxylation (ER) o Of Proline + lysine residues VITAMIN C CRITICAL Glycosylation (ER) o Of Pro-alpha-chain hydroxylysine residues + formation PROcollagen via H + DISULFIDE BONDS o TRIPLE HELIX of 3 alpha chains Exocytosis o PROCOLLAGEN extracell Proteolytic processing - CLEAVE terminal region = procollagenTROPOcollagen (insoluble) Cross-link - reinforce tropocollagen via covalent LYSINE-HYDROZYLYSINE CROSS-LINKSb (LYSIL OXIDASE) FIBRILS

2. 3.

4. Collagen 2 steps outside fibroblasts 5. 6.

Implicated genetic defect in osteogenesis imperfecta

Type I collagen disorder ColA1, ColA2 unstable collagen triple helix not as strong (phenotypic outcome depends on unique changes in genes) Glycine Proline Gly-X-Y where X = proline (or lysin/glycine), Y = hydroxyproline) Type III Reticulin (skin, vessels, uterus, fetal tissue, granulation tissue) Involved in forming collagen fibrils from pro-collagen triple helices that have been secreted into extracellular space *Copper-dependent Cross-linkage via covalently binding LYSINEHYDROXYLISINE Fibrils

2 MC AAs in collagen

Cartilage with PAS stain Lysyl oxidase

11

Cofactor requirement in early collagen synth

VITAMIN C 2 step (HYDROXYLATION) within fibroblast in ER Without = SCURVY Weakened vessels = ulcerated gums, tissue hemorrhage, anemia, wound healing, loose teeth, bone formation

nd

Elastin

Stretchy protein in lungs, large arteries, elastic ligaments, vocal cords, ligamenta flava (connect vertebrae for relaxed + stretched conformations) PROLINE, GLYCINE NONglycosylated forms Tropoelastin w/ fibrillin scaffold

Disease MC a/w elastin defect Elastase and associated disease

Marfans fibrillin gene **FIBRILLIN = large ECM proteins a/w elastic + non-elastic microfibrils Breaks down elastase normally balance break down/build up but in alpha-1antitrypsin excess elastin = EMPHYSEMA (panacinar) + CIRRHOSIS/liver failure (#1 cause liver transplant in newborns! Lesch-Nyan Alcoholism G6PD Hereditary fructose intolerance Galactose-1-P uridyle transferase def. (severe galactosemia) **all disoders with increased accumulation of phosphorylated sugars = degradation products (e.g. AMP uric acid) OVER-PRODUCTION Leukemia Myeloproliferative syndromes (MPDs) MM Hemolysis Neoplasia Psoriasis Alcoholism UNDER-PRODUCTION Renal failure ASA Diuretics Alcohol (all 3 categories)

Ddx uric acid + gout primary reasons

Ddx uric acid + gout secondary reasons

Direction DNA synthesis Direction RNA synthesis Direction DNA/RNA read Protein synth Actinomycin D Rifampin Interstitial deleting

5'3' 5'3' 5'3' (e.g. mRNA is read 5' 3') NC Binds DNA, preventing RNA polymerase from moving along template Binds B-subunit RNA polymerase, inhibits initiation RNA synth Large DNA fragment deleted on single chr pairing 2 genes not normally in sequence with one another (e.g. could bring activation one gene from another) Fusion oncogene Large large segment becomes reversed w/i same chromsome rearrangement post-breakage chr = fusion oncogene Binds K+ on Na/K pump, inhibiting Na/K ATPase Cardiac glycosides Direct bind/inhibit Na/K ATPase indirectly inhibiting Na/Ca exchange = Ca in cell = contractility NONSENSE mutation AA change generating 1 of 3 stop codons mRNA is transcribed correctly but during protein translation, would stop early (truncated, ineffective)

Chromosomal inversion Ouabain Digoxin/digitoxin

Normal amount of an enzyme present yet no enzymatic activity where is mutation?

Three stop codons

UGA UAG UAA (U Go Away, U Are Gone, U Are Away)

12

Test for carrier genetic disease Steps in testing Lyme Area where splice acceptor mutation occurs

PCR Amplify sequence of question and compare to normal ELISA first screening sensitive, rapid (can have false+) Follow-up with more specific WESTERN BLOT (protein) 3' end eukaryotic intron (invariant AG just before end intron) HIGHLY CONSERVED 5' end intron = GT (GU in RNA) necessary splice donor site Spliceosome removes introns recognizing GT at 5' + AG at 3' end = splice sites) mutation here greatly alters protein (B THALASSEMIA = SPLICING DEFECT chr11, HBB gene additional, contiguous length non-coding mRNA or

snRNP

discontinuous fragment = SNP SINGLE NT POLYMORPHISM)

Location cleavage propetides collagen Cofactor required by phenylalanine hydroxylase What "substance" crosses plasma membrane fastest? Extracellular first step; therefore is always "pro" type of collagen within cell Tetrahydrobiopterin *Defect in either PKU (MR, hypopigmentation) CO2, followed by O2 then nitrogen, inhaled anesthetics etc. E-cadherin diffusion is as rapid for these gases as it is for them in water CO2 has higher solubility vs. water

Allows formation of junctional complexes (critical for formation and maintenance) via homotypic interaction b/w each other (cadherins) that initiates formation zona adherens (including signaling paths) which are then activated to initiate formation zona occludens + desmosomes Transmembrane cadherin specific to zona occludens tight junctions Transmembrane cadherin specific to desmosomes e.g. forms intercellular linkages at desmosomes which connect epithelial cells PEMPHIGOUS VULGARIS anti-desmoglein Abs o Irregularly shaped erosions in GINGIVAL, BUCCAL, palatine mucosae o POSITIVE Nikolsky test apply pressure + epidermis appears to separate from underlying dermis o Bx: acantholysis w subsequent loss of cohesion

Occludin Desmoglein

Sites of synthesis proteins destined for lysosomal incorporation Bullous pemphigous vs. pemphigus vulgaris

RER Bullous =autoimmune IgG rxn vs. HEMIDESMOSOMES (collagen type XVII aspect) Pemphigous = DESMOGLEIN, tight junctions specific to epithelial cells, blisters, positive nikolsky, oral ulcers Alpha-1 agonists stimulate R on SM [Ca2+]in (IP3, DAG qiss Gq) contraction (constrict vessel) Muscarinic can induce NO release (aka EDRF endo relaxing factor); produced from arginine by endothelial cells A = NO CHANGE I = shorten H = shorten (think A is the best, so no need to improve, no need to ) A-spans width myosin thick filaments (INCLUDING overlap actin thin) length set by length of mysoin (thus no @ctx) H = thick myosin WITHOUT overlap actin I = actin filaments ONLY Z line where actin filaments attach

Action of alpha-1-adrenergic agonist (e.g. phenylephrine) on vessels vs. muscarinic

Muscle band changes during ctx A, I, H

13

MUST KNOW THIS too easy to not have on tip o tongue Calculating changing osmolarity Ex: cell with osmolality of 300mOsm/kg is placed in salt solution and grows to be 1.5x original size. What is osmolality soln?

MUST KNOW THIS too easy to not have on tip o tongue Mass solutes in cell dont change (while fluid volume does) Mass intracellular solute before = C1V1 Mass intracellular solute after = C2V2 C1V1 = C2V2 300mosm(1) x(1.5) X = 200

Diseases caused by DNA mutation/repair defects

KEY NER = NT excision repair, AR = recessive, AD = dominant

Dz
Xeroderma pigmentosum

Defect
NER

Inheritence
AR

Manifestations
r/o all skin CA (1,000x) incidence Japan

Tx
1. retinoids - CA but irreversible calcification tendons/ligaments - acitretin treats keratoses, also used in psoriasis 2. 5-FU (pyramidine analog antimetabolite) No cure supportive *CS2 worse than 1

Cocakyn's syndrome

NER

AR

Bird-facies (thin nose, small head, large ears) Retinopathy, dwarf with long limbs, photosensitive Hyperpigment, erythema, teleangiectasias Premature aging Sulfur Brittle hair/nails Fish skin scaly Physical/mental retardation BM fail w DNA repair defect - petechiase, bruise, pallor, caf-au-lait - infection, fatigue - aplastic anemia (pancytopenia), leukemia, solid tumors (CA liver, neck, esophagus, vulvar) growth w/ r/o malignancy Butterfly facial telangiectatic erythema -resp/GI infection Aging, thin, tight, scleroderma-like skin muscle, wrinkle, hyperkeratosis Cataracts, osteoporosis, arteriosclerosis, CA, DM Japan, M=F

Trichothiodystrophy

NER

AR

Rare, no cure

Fanconi's Anemia

ROS DNA repair Cycle ctrl

AR 11 genes

Tx symptoms (anemia/leukemia/CAs)

Bloom

Helicase Chr. Instab.

AR

Werner's

Helicase (WS gene)

AR

First 10 yrs of life normal death 40yo No tx

14

ATAXIA-TELANGIECTASIA

Chromos + chromatid breaks w rearrangmt

AR chr 7 + 14, ATM gene **(= TCR + Ig regulation chr)** AD MSH2, MLH1, (PMS2), Ras genes AD BRCA1

Heterogenous, but marked by neurodegeneration (ataxia) + telangiectasia (2/2 dilation vessels) - sino-pulm infections r/o CA, sensitive to xrays/radiation Change in # of repeats of germline alleles accumulation mutations 80% r/o CRC Females have 30-50% r/o endometrial 60-80% r/o serous adenoCAs BRCA 2 = ovarian, prostate, pancreatic

Treat Sx Death teens

HNPCC/ LYNCH SYNDROME

Mismatch repair Microsat. Instability p53 DNA repair, cycle

C'scope q2yr at 25yo, q1yr @40yo (colectomy usual at this pt) **L colon>R colon unusual** CA tx same as regular breast CA but can do ppx mastectomy

BREAST CA

GENETICS
Blotting which for what SNoW DRoP S = DNA N = RNA W = Protein Southwest = DNA-binding proteins (TF factors) Blot that allows determination of whether absence of protein is due to failure gene transcribed vs. post-transcriptional defect Technique used to separate false positive HIVELISA from true positives Uses DNA-DNA hybridization This makes sense DNA = South, TF=Protein = West Use labeled oligoNT probes Isolate RNA from PMNs gel, blot, 32-P-DNA probe for specific gene Western blot Southern blot Indirect geenetic testing within families, relatedness of individuals, determination epidemiologic relatedness of bacterial biotypes, e.g. strains S aureus producing TSS

Northern blot

Blot that gives semi-quantitave result for level of gene expression in tissue

Northern blot

15

Microarray use (for usmle at least)

SNP detection (single NT polymorphisms) to study dz/tx Genotyping Forensics Predisposition to dz Cancer mutations Genetic linkage analysis

*detecting relevant amt complementary nucleic acid sequences to dna/rna probes Test used to test for antibodies ELISA Two methods: 1. 2. Uses of FISH Pts blood + test antigen (coupled to enzyme probe) does pts immune system recognize? Pts blood + test antibody (coupled) is antigen present?

Most sensitive/specific for HIV 100% each Microdeletions at molecular level (when deletion too small to see on karyotype Fluorescent gene is present None = gene has been DELETED Steps in production recombinant DNA (for cloning) Isolate eukaryotic mRNA (post-RNA processing) Expose to reverse transcriptase cDNA Insert cDNA into bacterial plasmid containing antibiotic resistance genes surviving bacteria on Ab medium produce cDNA library

Conditional vs. constitutional transgenic mice

Conditional = targeted insertion/deletion gene via homologous recombination Constitutive = random insertion gene into mouse genome dsDNA made to separate + degrade target mRNA Synthesized to complementary mRNA Metaphase Characteristic with loss-of-function in mismatch repair genes (hMLH, hMSH HNPCC, endometrial CA, ovarian CA, gastric CA) Areas of diNT repeats a/w "slippage" @replication that s number of repeats on new strand (=instability) o Mismatch repair genes would normally fix *Normal microsatellites can be 2-4bp totaling <150bp total (repeats = instability)

RNAi When in mitosis do you stain for karyotyping? Microsatellite instability

Lab technique that is best at detecting whether disease is heritable form (E.g. gene deletion) or sproadic Method of coupling Abs to fluorescent markers to determine cell surface markers of whole cells, e.g. CD34+ stem cells Term - Codominance Term variable expression Term incomplete penetrance

PCR can see size DNA of amplified band If INHERITED ALL CHROMOSOMES in body will show shorter allele WHEREAS SPORADIC will ONLY have abnormal/short allele IN TUMOR tissue/cell-types FACS

Neither of the 2 alleles are dominant Blood groups (A, B, AB) O is "no allele" Nature + severity phenotype vary 1 personanother 2 pts w/ NEUROFIBROMATOSIS may have varying severity Not all individuals with mutant genotype show mutant phenotype

16

Term pleiotropy

1 gene > 1 effect on person's phenotype (sort of opposite locus heterogeneity) PKU causes many seemingly unrelated symptoms (MR hair/skin s) OSTEOGENESIS IMPERFECTA (excess atypical fx, scoliosis, basilar skull deformities, blue sclerae, opalescent teeth, skin laxity) Diff in phenotype depends on whether mutation is of maternal vs. paternal origin PRADER-WILLI Dad "happy puppet" ANGELMAN'S Mom hyperphagia + obesity Chr15* Patient inherits/develops mutation in tumor suppressor gene then the COMPLEMENTARY allele must be deleted/mutated BEFORE CA develops RETINOBLASTOMA (Rb p100) Exerts DOMINANT EFFECT heterozygote has non-functional altered protein that prevents normal gene product from functioning MUTATION of TF in its ALLOSTERIC SITE nonfunctioning mutant can still bind DNA thereby PREVENTING wild-type TF from bnding Tendency for certain alleles to occur together more often than expected by chance Measured in population NOT family + varies between different pops Occurs when cells in body have different genetic makeup Can be germ-line mosaic can produce disease not carried in parent's somatic cells

Term - imprinting

Term loss of heterogeneity

Term Dominant negative mutation

Term linkage disequilibrium

Term - Mosaicism

LYONIZATION- random X inactivation in females DOWN'S trimsomy w/ mosaicism 47, +21 /46 -2-3% Down's, less severe

phenotype (IQ etc) has half normal cells, half not NON-disjunction chr21 occurs DURING MITOSIS NOT MEIOSIS in an early cell division)
Term Locus heterogeneity Mutations at different loci produce same phenotype (Sort of opposite pleiotropy) *MARFAN'S, MEN 2A/B + HOMOCYSTEINURIA all cause MARFINOID HABITUS *ALBINISM (+ acular type e.g. color-blindnessb) *OSTEOGENESIS IMPERFECTA (type 1 procollagen chr7 OR chr 17 BOTH lead to imperfect formation trimeric protien) Presence both normal + mutated mtDNA = variable expression in mitochondrial inherited dz LEBER'S HEREDITARY OPTIC NEUROPATHY degeneration retinal ganglion cells + axon leading to acute loss vision Term uniparental disomy Offspring receives 2 copies chr from 1 parent and no copies from other

Term heteroplasmy

17

NONDISJUNCTION meiosis 1 vs. 2

NONDISJUNCTION = failure of paired chromosomes to separate + go to diff daughter cells leading to one daughter cell getting extra chromosome (n+1) while the other is one chr "short" (n-1) MEIOSIS I - if NONDISJUNCTION HERE child will get 3 different copies of gene (2 from 1 parent + 1 from other parent) b/c homologues carry SIMILAR but NOT IDENTICAL info MEIOSIS II sister chromaatids (2 identical copies SAME chromosome) should separate if NONDISJUNCTION HERE 2 copies SAME EXACT chrosome passed to progeny (e.g. 1 allele x2 from 1 parent and one from other) SUM if mom has alleles A+B, dad has C+D if kid gets A, B, C = meiosis I A, A, C = meiosis II RFLP (restriction fragment length polymorphism) can detect region near centrosome of a chromosome (E.g. chr21) surrounding region exhibits crossover suppression genetic exchange canNOT occur in this area and so probe = reliable marker individual chromosome

Reciprocal vs. Robertsonian translocation

Reciprocal: true exchange DNA chrchr (fragments b/w chromosomes) FUSION GENE or CHANGE EXPRESSION existing gene BCR-ABL 9;22 CML Robertsonian: large fragment 1 chr another WITHOUT a "return" of DNA (e.g. nonrecipricol) ACROCENTRIC CENTROMERES ( o 13, 14, 15, 21, 22 Minority DOWN's has 2114 robertsonian (MCC Downs = trisomy)

3 DIFFERENT types Down's inheritance

1. 2.

3. Pedigree with horizontal transmission

Trisomy 21 (47, +21) - MCC Trisomy MOSAICISM 21 (47, + 21 / 46) 2-3% a. 2 "populations" of cell types normal cell line (46 chrs) AND nd 2 line w/ trisomy 21 i. Less extreme phenotype (e.g. IQ) Robertsonian translocation (2114)

AR all effected are in same generation, e.g. unaffected parents but affected kids 25% offspring 2 carrier parents affected, see in one generation only (usually) Commonly more severe than AD disorders shows up in childhood Often PLEIOTROPIC, presenting after puberty FH crucial to dx

Pedigree with vertical transmission

AD 50% offspring affects, across generations -

Pedigree x-linked recessive

M > F (female must be homozygous), but dad never passes on to his son (e.g. NO malemale transmission) 50% sons to MOM CARRIER affected (heterozygoous mom)

Pedigree x-linked dominant Example x-linked dominant

*If DAD is affected ALL DAUGHTERS affected *If MOM is affected Sons and daughters MAY be affected HYPOPHOSPHATEMIC RICKETS (formerly = vitamin-D-resistant rickets) phosphate wasting PROXIMAL TUBULE

rickets-like presentation
Heteroplasmy Normal AND mutant MITOCHONDRIAL DNA (mtDNA)are expressed

18

Ex of mitochondrial inheritance + genetics inheritance

*transmission via mom only all offspring (M/F) may have signs dz **often d/t failure oxidative phosphorylateion Variable exprssion d/t heteroplasmy LEBERS HEREDITARY OPTIC NEUROPATHY acute loss of central vision MYOCLONIC EPILEPSY MITOCHONDRIAL ENCEPHALOPATHY MITOCHONDRIAL MYOPATHIES

"RAGGED RED FIBERS" on microscopy Female who is heterozygous for X-linked recessive gene can sometimes have mild expression of disease phenotype - how? X inactivation is random event normally, female has enough "normal" phenotype b/c on average, of cells will express normal allele HOWEVER, extrae degrees of X-chr inactivation can lead to predominance one allele can express gene G6PD mild anemias Hemophilia mild bleeding Female expressing FULL phenoytype of x-linked recessive disease Hardy-weinberg Possible if concomittant TURNER'S SYNDROME (SHORT stature etc) since only 1X WILL SEE ABNORMAL KARYOTYPE will see a missing sex chr p + 2pq + q =1 p+q=1 generally, given disease freq 2 (p ) or allele freq (p) if GIVEN disease freq, than 2 calculate mutant allele freq = p = p Using, p, find normal allele freq = 1-p = q Now can determine carrier freq = 2pq or if asked to predict FUTURE baby given just one partner, using the calculated p+q AND BE SURE to account for various possible outcomes as you would with ANY baby problem e.g. if asking about baby carrier status to a heterozygote + normal person, than know it is 50% but nd if you DONT know status 2 partner, use allele freq population as frequency that gene in partner (almost as though treating like variable penetrance) see below problem Given that 1 partner is heterozygous for an autosomal recessive trait (pq) and the frequency of dz (A), AND NO OTHER INFO, how could you predict the chance that the partner will have a diseased baby without knowing the other partner's status? If frequency of dz = A,, then a = p 2 2 2

allelic frequency = A this will also be EQUAL TO frequency egg carrying the recessive allele (a, or pA) if 1 partner is KNOWN CARRIER, there is 50% of passing on recessive allele thus, chance that he will have a child with the disease = (0.5)( A), i.e. (0.5p)
nd

with numbers: if 1% population has X and 1 partner is carrier, 2 partner status unknown 0.01= p p = 0.1
2

19

Change in H-W equation if disease is X-linked

Males hemizygous = 1 allele FREQUENCY OF ALLELE will be EXACTLY THE 2 SAME as the GENOTYPE e.g. q = q (incidence dz = incidence allele) MALES: p + q = 1 is equation expressing allele freq AND gen. freq 2 2 FEMALES: p + q = 1 allele freq ONLY; for gen. freq, need p + 2pq + q =1 "The incidence of DMD in N. America is 1/3000. Based on this frequency, what is the gene frequency of this trait?" 1/3000! **ON EXAM, BE CAREFUL they will not say "THIS IS X-linked" so PAY ATTENTION to the DISEASE BEING MENTIONED do not go right to equation b/c it changes If x-linked (x-linked = Boys Wish For Hannah's GOLD Hockey Skills bruton's agammaglobulinemia, wiskot-aldrich, fabry's, hemophilia, G6PD, ocular albimism, lesch-nyhan, duchennes(+beckers), hunters syndrome)

ASSUMPTION MADE IN H-W EQUATIONS

P=1

**DONT FORGET TO MULTIPLY BY 2 TO GET CARRIER FREQUENCY after calculating q (carrier = 2pq and if p=1, carrier = 2q)

LINKAGE DISEQUILIBRIUM Genetic drift vs. gene flow

Preferential association of allele at one locus with another allele at nearby locus more frequently than be chance alone DRIFT gene frequency d/t FINATE population size would ONLY SEE in small/closed communities FLOW gene exchange b/w different populations

20

WORKING THROUGH ALPHA-THAL genetics

27yo Asian-American male comes to ED with RUQ abdominal pain + nausea. Studies show mild, microcytic hypochromic anemia + target cells. Has a ____ who died at birth from blood disease and uncle with HbH. Wife has completely normal blood. Chance that patient will have carrier child. We know that BOTH parents must have one completely normal alpha/alpha allele and one completely abnormal - - / - - allele to have had hydrops baby. Because patient is presenting with symptoms, can assume he carries trait, e.g. 2 bad alleles out of 4 AND since he is living must have one full normal + one full abnormal e.g. ( a a / - -) will have 50% chance passing on (a a) allele and 50% chance of passing on bad ( - -) allele. Since wife is clean, 50% chance child will have trait

*NOTE* the double mutant allele (a a ) is MC in asian population. Otherwise, more frequently have trait with (a - / a - ) or silent carrier (a - / a a ) **REMEMBER** 2 variations "alpha-thal trait" (a a / - -) OR (a - / a - ) 2 alleles HbH = (a a / a - ), Hydrops = (a a / a a) 3 + 4 alleles Silent carrier = ( a - / a a) 1 allele

Disorders by mutated gene/function (see separate "Chromosomal" table too)

ATM gene mutation ATAXIA TELANGIECTASIA (as name implies) multiple dilated vessels + progressive ataxia Gene kinase responsible for recognizing/correcting errors in duplicating DNA during cell division normal = repair ds DNA break mutant = sensitivity ionizing radiation frequent chromosomal abnormalities incidence MALIGNANCIES ESPECIALLY lymphoreticular (these cells are dividing most frequently) = HL, NHL, leukemias XERODERMA PIGMENTOSUM UV light sens freckles, skin CA, corneal ulcerations Gene thymine dimer repair via nick PDE bond on strand w/ dimer on both sides + removes Defect dimers persist

Excision endonuclease

21

Splice site mutation (5' UTR of ATP7B gene)

WILSON'S Copper accumulation (d/t absence ceruloplasmin) in liver, brain, cornea - Asterixis - BG degeneration producing parkinsonian sx -Kayser-Fleisher rings corneal deposits 1. 2. TRISOMY 21 (47, +21) - MCC Trisomy MOSAICISM 21 (47, + 21 / 46) 2-3% a. 2 "populations" of cell types normal cell line (46 chrs) nd AND 2 line w/ trisomy 21 nl, not i. Less extreme phenotype (e.g. IQ)

DOWN's

3.

NON-disjunction chr21 occurs DURING MITOSIS NOT MEIOSIS in an early cell division) ROBERTSONIAN TRANSLOCATION (2114)

DOWN'S trimsomy w/ mosaicism 47, +21 /46 -2-3% Down's,

Chromsomal disorders - specific chromosome locations Disease ChromOsome 7 AR Gene CFTR F508 (phenylalanine delete) Manifestations Protein misfolded and improper oligosacch additions at endoplasmic reticulumproteasome (degredation) instead of plasma membrane Pseudomas, S. aureus infections PNA, bronchitis/bronchiectasis Pancreatic insuff, steatorrhea, VitA/D/E/K def Male infertility Biliary cirrhosis, meconium ileus

CYSTIC FIBROSIS

Dx NaCl on sweat test; PCR + ASO probes Tx enzyme + vitamins etc N-acetylcysteine (LOOSENs mucus plugs CLEAVES disulfide bond w/i glycoproteins)

MEN 2A/2B

10 AD

RET RTK that binds neutrophic factors that signal cell to grow+divide (gain of function/activating) **OTHER RET = hirschsprungs

BOTH 1.medullary thyroid CA 2. pheochromocytoma; plus A=pituitary adenoma B=oral/facial ganlioneuromatosis (e,g, mucosal neuromas- LIPs) +marfinoid

PRADER-WILI VS. ANGELMAN CRI-DU-CHAT

15q11

(deletion in area affected by imprinting)

Maternal deletion (With silent, methylated father allele) = AngelMans (happy puppet) Paternal deletion (silent/methylated mom allele) = Prader-Willi (MR, hyperphagia+obesity with initial poor feeding) High pitched monotonic cry Microcephaly, wide-set eyes, MR Epicanthial folds CARDIAC ABNORMALITIES, e.g. VSD

5q

microdeletion

LI-FRAUMENI

AD

p53 Loss-of-function mutation/deletion tumor suppress gene

r/o breast CA, colon CA, soft-tissue sarcoma, osteosarcoma, brain tumors, leukemia + adrenocortical CA

22

MICROSATELLITE INSTABILITY (2+)

AD w/ variable penetrance 22q11

hLMH1 + hMSH2 mismatch repair genes

MC association = HNPCC but also in: Endometrial CA Ovarian CA Gastric CA

DIGEORGE

*thymus structural/functional defect; missing T-cell immunodeficiency *hypoparathyroid = 2 hypercalcemia *craniofacial abnormalities, palate Glutaminevaline @position 6 in Beta-globin gene Microdeletion NF2 tumor suppressor gene Malignant urinary tract tumor 2/3 dx by 4yo Surgical removal

SICKLE CELL WILMS TUMOR

AD 11p13

NEUROFIBROMAT
OSIS

17 AD

NF1 tumor-suppressor gene

90% NF cases (vs. type 2) Multiple neurofibromas Caf-au-lait Lisch nodules pigmented iris hamartomas r/o pheochromocytoma + mengingiomas BILATERAL acoustic neuromas (schwanomas is tip-off) otherwise, the rest are both NF1/2: Neurofibromas Caf-au-lait r/o meningioma+pheo Marfinoid habitus tall, hyperextensible, pectus excavatum + kyphoscoliosis Subluxation lens Heart defects o Cystic Medial Necrosis of aorta o Dissecting AA o Valvular insufficiency Mitral regurg = holosystolic murmur in apex o MVP = midsystolic click) Hemangioblastomas CNS + RETINA RENAL CELL CA Cysts internal organs Sebaceous adenomas (Angiofibromas of sebaceous glands) o Subependymal nodules = LISCH NODULES Epilepsy MR dysplastic white matter lesions = Hamartomatous lesions skin, CNS, viscera Cortical tubers Shahreen patches (see picture -- -- --- --- Ash-leaf spot (hypomelanic, light patches, Wood's) RENAL ANGIOMYOLIPOMAS

TYPE 1 (VON
RECKLINGHAUSEN)

NEUROFIBROMAT
OSIS

22 AD

TYPE 2

MARFAN

15 AD

FBN1 fibrillin 1 **FIBRILLIN = large ECM proteins a/w elastic + non-elastic microfibrils

VON HIPPELLINDAU (VHL) TUBEROUS SCLEROSIS

3 AD AD

VHL = tumor suppressor gene

TS 1/2

Heart Defect RHABDOMYOMAS

23

OSTEOGENESIS
IMPERFECTA

("BRITTLE BONE")

7 or 17 - locus heterogeneity AD

COL1A1/2 type 1 procollagen

**PLEIOTROPY** - blue sclerae seemingly unrelated to fx **LOCUS OF HETEROGENEITY** 2 diff single chromosome mutationssame dz Looks like child abuse Multiple fx w/ minimal trauma BLUE SCLERA (translucent CT over choroid) Hearing loss (ABNL MIDDLE EAR BONE) DENTAL lack dentin

*remember I = Bone, Skin, tendon Type ONE = BONE

EHLERS-DANLOS

AD and AR many types

COL3A Type 3 collagen

Hyperextensible skin Easy BRUISING/Bleeds Hypermobile jts

**6 types w/ varying inheritance/severity (AD or AR) +/- a/w: Joint dislocation BERRY ANEURYSM Organ rupture

*remember III = Reticulin = skin, vessels, uterus, fetal tissue, granulation tissue Type III = ThreE D defective in Ehlers-Danlos

ATAXIATELANGIECTASIA

Chromos + chromatid breaks w/ rearra ngmt

AR

AR chr 7 + 14, ATM (PI3 kinase) that phosphorylate >700 proteins in DNA repair* inc. p53 + BRCA-1 tumor supp ( chrs correspond to = TCR + Ig reg)**
WS gene helicase error

Heterogenous, but marked by neurodegeneration (ataxia) + telangiectasia (2/2 dilation vessels) - sino-pulm infections r/o CA, sensitive to xrays/radiation

(WERNERS)

Aging, thin, tight, scleroderma-like skin muscle, wrinkle, hyperkeratosis Cataracts, osteoporosis, arteriosclerosis, CA, DM Japan, M=F BM fail w DNA repair defect - petechiase, bruise, pallor, caf-au-lait - infection, fatigue - aplastic anemia (pancytopenia), leukemia, solid tumors (CA liver, neck, esophagus, vulvar) - Tx symptoms (anemia/leukemia, etc) UV light sens freckles, skin CA (1,000x), corneal ulcerations incidence Japan Tx: 1. retinoids - CA but irreversible calcification tendons/ligaments - acitretin treats keratoses, also used in psoriasis 2. 5-FU (pyramidine analog antimetabolite) Normal gene thymine dimer repair via nick PDE bond on strand w/ dimer on both sides + removes Defect dimers persist

FANCONI

AR

11 genes DNA repair, ROS vulnerability, Cell cycle dysregulation

XERODERMA
PIGMENTOSUM

AR

Excision endonuclease thymine dimer repair

BREAST CA ALS

AD AD

BRCA 1 (2 = ovarian/ prostate/ pancreatic) SOD1 copper/zinc superoxide dismutase

60-80% r/o serous adenoCAs

24

MENKE'S (TYPE 4 EHLERSDANLOS)

Xlinked

ATP7A ATP-dependent copper transport protein

Ehlers-Danlos type 4 "collagen" connection is due to requirement copper co-factor for lysyl oxidase (final steps collagenin EC space) defective copper transport + abnormally activity copper-dependent enzymes (one of which is lysyl oxidase) with ceruloplasmin levels -depigmented, lusterless hair = "KINKY HAIR" - osteoporosis, anemia - facial/ocular/vascular/cerebral manifestations (think head-up + vessels, which always comes with collagenous dz) "A 4mth old boy appeared healthy at birth but now has poor growth, feeding and delayed developmental milestones. PE shows listlessness + matted, sparse + very pale hair"

HUNTINGTON

4 AD

CAG triNT repeat

Depression Progressive dementia Choreiform CAUDATE ATROPHY GABA + ACh in brain 20-50yo

SICKLE CELL FAMILIAL

ADENOMATOUS POLYPOSIS

AR APC - tumor suppressor gene

RETINOBLASTOMA

AD w/ variable penetrance 7q 3 AD 5 AD Xlinked

Rb - tumor suppressor gene **ALSO IN OSTEOSARCOMA**

WILLIAM'S
DISEASE

Elastin (microdeletion) FGF-R3 - cell signaling defect APC deletion Dystrophin LARGE DELETION single gene vs. pt mutation same gene

Elfin facies, HYPER-Ca 2/2 sensitivity to vitD), good verbal, very friendly, heart issues Dwarf, short limbs, but normal head/trunk size **a/w advanced paternal age - >puberty, colon covered with polyps - CRC always if not resected /(usually ~40yo) DUCHENNE = frame-shift = DELETION dystrophin gene accelerated muscle breakdown - Onset <5yo = pelvic girdle weakness (need UE helpto get out of chair sign = COWERS) progresies superiorly - PSEUDOHYPERTROPHY CALF muscles 2/2 fibrofatty replacement muscle - Cardiac Myopathy - Dx = CPK, muscle biopsy - **Dystrophin Gene (DMD) = helps anchor muscle fibers (skeletal + cardiac) - LONGEST known human gene rate spontaneous mutation BECKERS = IN-frame deletion or insertion - less severe, some functional gene made - Onset adolescence early adult **SUBCLINICAL FEMALES** - heterozygous carriers have degeneration fibers

2+

ACHONDROPLASIA FAP DUCHENNE'S MUSCULAR DYSTRPHY VS. BECKER'S

ADPKD

16 AD

APKD1 (90%)

*ALWAYS BL, massive kidneys d/t multiple large cysts *Present flank pain, hematuria,HTN, RF

25

FAMILIAL HYPERCHOLESTER OLEMIA (TYPE IIA)

LDL 2/2 defect/absent LDL-R **Heterozygotes (1/500) = 300 **Homozygotes (RARE) = 700+ - Severe atherosclerotic dz early in life - TENDON XANTHOMAS (achilles) - MI <20yo

HEREDITARY HEMORRHAGIC TELANGIECTASIA (OSLER-WEBERRENDU) HEREDITARY SPHEROCYTOSIS MYOTONIC DYSTROPHY

19 AD (can be spont.) Spectrin OR Ankyrin CTG triNT in protein kinase

BLOOD VESSELS Telandiectasias Recurrent epistaxis Skin discoloration AVMs

Spheroid RBVs d/t hemolytic anemia + SPLENECTOMY CURATIVE MCHC MyoTonic = CTG (vs. CGG = fracile X) Clinically UNIQUE: Weakness Atrophy Myotonia (tonic ctz) Head+neck often most weak/atrophic

WONT RELEASE HAND WHEN YOU SHAKE

FRAGILE X

Xlinked (xq27)

CGG triNT repeats FMR-1 gene

r/o CHROMOSOMAL BREAK nd st 2 MCC MR (1 = Downs) MACROCHORDISM (big testes), long face, LARGE + everted ears, autism, MVP* (Fragile X = Xtra larges teses/jaws/ears) IN ADDITION to TRI-nt rpt exp, also role of DNA METHYLATION Dx = >4% metaphase chromosomes must show specific break-pt on X chr (percentage above 4% does NOT correlate w/ severity MR)

FINAL MIX GENETICS, MOBIO, CELL BIO

Child with poor eye contact and HAND FLAPPING If 1/100 ppl have disease A which is AR, what is carrier population freq? Calculating changes in volume with compartments of different salt concentrations Mediator of lysosomal enzyme delivery to lysosomes Given phenotype that is related to inheritable tumor, best lab test to determine if it is due to inherited mutation or sporadic mutation? Fragile X CGG repeat 1/2 (1/100) = 1/10 = p 1 1/10 = 9/10 = q 2pq = 2(9/10)(1/10) = 18/100 C1V1 = C2V2 (before and after change in environment) Key is that Mass = C x V and this remains constant Clathrin-coated vesicles PCR the cells in an inherited disease will all show the different (mutant) DNA allele size as all cells came from same progeny - cells in sporadic disease will only have abnormal IF you are testing cells from tumor tissues all other, non-involved cells will only provide alleles of normal size 1. Concomitant Turner 45X,0 (hints include a short stature, female 2 sex characteristics) this is similar to being male with only 1 X copy 2. 2 copies mutant X gene must be a disease that does not affect fathers fertility, such as G6PD Klinefelters XXY only ones with two Xs, thereby leading to inactivation of one (Barr) nd - NOT Turners 45XO (even though this is female missing 2 x chr means no Barr) -

2 ways that a female can exhibit phenotype of Xlinked recessive mutation

Common sex chromosome aneuploidy that would have fetal tissue expressing Barr bodies

26

Type of chromatin in mitotically dividing cell

Heterochromatin (closed/wrapped; euchromatin = open for active transcription)

Part of cell cycle where triNT repeats in number Adolescent boy with recent h/o burning + tingling of hands found t have corneal opacities + angiokeratomas (benign cutaneous lesion of capillaries = small marks red/blue color ) Cellular component mitotic spindle Cellular component microvilli Cellular component cilia Child diagnosed with an AD disease (e.g. Marfans) with no family history what is most likely cause? What does CREB, SP-1, RNA polymeras, + steroid receptor have in common If membrane protein seen in RER but not membrane or cytoplasm Infant with hyperplastic gums, lethargy, misshapen long bones, restricted jt movements, st corneal clouding, parents are 1 cousins Protein critical in formation + maintenance junctional complexes such as the tight junctions between enterocytes Action of hammerhead ribozymes Gas that diffuses fastest across lipid membrane

S (synthesis) Fabrys Boy = x-linked

Microtubule ACTIN (+ myosin by extension) Microtubule (9+2 arrangement dynein think Kartageners) New mutation transmitted by one parent to affected child All are TFs or modulators of transcription on DNA for regulation of protein synthesis Misfolding ubiquination + degradation path (proteasome) I-cell disease Defective phosphorylation of mannose moieties lyosomal enzymes not targeted to lysosome = serum levels acid hydrolases + glycosylases E-cadherins Occludins = zona occlude Desmogleins = specific junction protein in epithelial cells (pemphigus vulgaris w mouth ulcerations) Degrade mRNA (catalase activity) of which they have homologous sequence (to bind) CO2, followed by O2, then all others (e.g. nitrogen)

Effect of a mutation AG CG at 3 end eukaryotic gene intron Listless infant with matted, sparse, pale hair, poor growth, developmentald delay

Substrate in synthesis of carbohydrate chains that are transferred to protein component of glycoproteins such as albumin Hexosaminisae A deficiency Capping of mRNA

Abnormal splicing AG = highly conserved (invariant)) spliceasome acceptor site sequence at 3 end all introns (matches this with preceding 5 GT (GU in RNA) seq) activity LYSYL OXIDASE = MENKES X-LINKED (Ehlers Danlos type 4, ATP7A mutation) - defect copper transport = activity Cu-dependent enzymes with ceruloplasmin levels **DEPIGMENTED LISTLESS/KINKY HAIR is biggest tip off Dolichol

TAY-SACHS Cherry red macule without hs-megaly (N-P) st Occurs immediately after synth 1 30 NTs (e.g. before transcription even finishes since read 53 will be done earliest) GTP condenses w/ available 5 diphosphate on growing RNA chain forms GUANINE CAP Cap recognized during protein synteshsi Protects RNA from degradation

27

 cytochrome b5 reductase

= IRON-dependent enzyme, aka NADH methemoglobin reductase major pathway that reduces methemoglobin which forms spontaneously with oxidative stress etc. Deficient METHEMOGLOBINEMIA cyanosis (nl amt <1%) 2= 3+ - metHb = OXIDIZED form Hb (Ferrous Fe Ferric Fe ) = affinity O2 (curve shifts LEFT) unloading O2 at tissue (blood has O2-carrying capacity, turns brown) can arise in pts with PK def d/t impaired NADH production = ESSENTIAL COFACTOR of enzyme or in G6PD def d/t impaired NADPH cofactor * (Also is recessive genetic defect in chr or can occur with abnl Hb variants, e.g. HbM or HbH) *remember oxidized = less electrons, reduced = more, so Fe3+ has MORE positive charge/less electrons = oxidized* CAUSES OF ACQUIRED METHEMOGLOBINEMIA Exogenous oxidizing Rx + metabolites - rate formation metHb overwhelms protective systems = acute metHb levels o benzocaine o dapsone o nitrates 2. ABX a. TMP b. Sulfas c. Dapsone 3. Local anesthetics a. Articaine b. prilocaine 4. ANILINE DYES (polyurethane, indigo; normally a/w BLADDER CA) 5. Metoclopromide DA-blocking Antiemetic (D2-R antagonist with mild 5HT-3 antagonism + some anti-muscarinic effects) a. ALSO gastric emptying in gastroparesis good antiemetic for DM pts); stimulates lactation) b. Parkinsonian SEs, contra in SBO 6. Chlorates, bromates 7. Nitrate ingestion (bismuth nitrate) BLUE BABY SYNDROME in babies drinking contaminated water from FERTILIZER nitrates a. Babies also get from dehydrration 2/2 diarrheal GE, sepsis, topical anesthetics w/ benzocaine, prilocaine (benzocaine also often in baby teething gels applied to gum/throat) *Tx Methylene Blue IV (or flavin) then normal saline flush (= artificial eacceptor for NADPH methemoglobin reductase (enzyme function at 5x nl) NADPH generated via HMP shunt RESTORES Fe3+ Fe2+ =normal/reduced O2-carrying state) levels glutathione peroxidase MYOPATHY + CM MENKES (E-D type 4, x-linked Cu-enzyme def., lyosyl oxidase) PKU 1.

Selenium deficiency 2 congenital diseases with MR + skin hypopigmentation (not neurocutaneous)

28

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EMBRYO

PATHOLOGY + MISCELLANEOUS Analine dye association URINARY BLADDER CA industrial workers (also shistosomal parasites outside of US with general RFs = smoking, exposure to certain chemicals + parasiteic infection) Also a/w methomologbloinemia

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Points of exit for Trigeminal nerve Standing Room Only: V1 - Superior orbital fissure V2 - foramen Rotundum V3 - foramen Ovale Extensor Compartment of the Arm Beer Eating CReoLe Eating CRaB Eating Dog Eating Dog's Mother Even Cathy's Underwear Brachioradialis Extensor Carpi Radialis Longus Extensor Carpi Radialis Brevis Extensor Digitorum Extensor Digiti Minimi Extensor Carpi Ulnaris

Great vessels- ABC'S of the aortic arch: Aortic arch, Brachiocephalic trunk, the left common Carotid, and the left Subclavian artery Thoracic duct The duck is between two gooses: duck = thoracic duct 2 gooses = azyGOUS vein and esophaGOUS Order of structures in groin (from lateral to medial) NAVEL Nerve, Artery, Vein, Empty space, Lymphatics Carpal bones Some Lovers Try Positions That They Can't Handle Scaphoid, Lunate, Triquetrum, Pisiform, Trapezoid, Trapezium, Capitate, Hamate. Gluteal Muscles Rhmye Time: "Tensor Fasciae Latae, Gluteus Med & Min...first abduct the femur, then rotate it in." All other gluteal muscles are lateral rotators of the femur. BONUS: Tensor Fasciae Latae, Gluteus Minimus, and Gluteus Maximus are all innervated by the Inferior Gluteal Nerve. Radial nerve "BEST" It innervates the Brachioradialis, Extensors, Supinator, Triceps. Median nerve "LOAF" It innervates the Lateral 2 Lumbricals, Opponens pollicis, Abductor pollicis brevis, Flexor pollicis brevis. Brachial Plexus Lesions "DR. CUMA" D - wrist Drop (is caused by...) R - Radial nerve lesion C - Claw hand (is caused by...) U - Ulnar nerve lesion M - Median nerve (lesion causes...) A - Ape hand Mitosis People Meet And Talk, or PMAT Prophase, Metaphase, Anaphase, Telophase.

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