Basic Science quick facts step1

BS Hard-to-Remember updated 6/9 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 (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 – HETEROCHROMATIN – condensed, tightly wrapped around histones vs. vs. loosely-packed transcriptionally active euchromatin)

1. Gene X is on opposite strand  sequence will run in

opposite direction near first exon gene X "  2. start codon ATP7B is " near "   5'UTR 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 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

 fusiform,  fusiform, spindlelongitudinal, the normally "  shaped" SM cell  appears round BUT round BUT STILL SHOULD ID THIS EASILY given it's LOCATION b/w  ADVENTITIA  ADVENTITIA + INTIMA INTIMA (e.g. thus = media)

1

DO GEL READINGS QUICKLY – 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 ) that ) + then just switch to complementary NT (eg A T) – T) – 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

2

BIOCHEM Chronic arthritis, black urine

Alkaptonuria Tyrosine

Liver and kidney dz 2/2 AA issue

Tyrosinosis

Albinism

Tyrosine def.  melanin Pale hair + ↑r/o melanoma/skin ca

Pale hair + skin, MR, musty smell

Phenylketonuria (AR) 

Phenyalaninetyrisone deficient (phenyl enzyme or TB4 coenzyme)

Branched AAs

Isoleucine Leucine Valine Maple syrup urine dz – dz – CNS, MR, death, sugar-smell diaper) *"I Love Vermont maple syrup"

MR, osteoporosis, marfinoid-habitus, lens subluxation

Homocysteinuria ↑↑methionine/ ↑↑methionine/↓↓ ↓↓cysteine cysteine (cysteine (cysteine becomes essential AA) AA)

What RBC changes would you expect in a female who presents with an inherited hemolytic anemia

Inherited HEMOLYTIC anemia HEMOLYTIC anemia = 1. G6PD deficiency or 2. PK deficiency  If woman, woman, unless information given to suggest x-linked (and then kinase since this is not sexreceiving 2 “bad” x’s), most likely pyruvate kinase linked (AR)  NO Heinz (these are in G6PD – 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 (more offloading, LESS pickup - (REMEMBER, fetal Hgb, HbF has 2,3BPG to allow for affinity/more pickup from mom) Heritability familial hypercholesterolemia

AD

MOLECULAR + CELL BIO RER

Chaperones

   

secretory/exported proteins – 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)

Class of specialized proteins that function to assist proper folding newly synthesized proteins (properGolgiplasma 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 the protein ) on membrane (e.g. all is good until RER)

 – calnexin, calreticulin Ex  – SER

  

STEROID synth DETOX rx, DETOX rx, poison ↑ hepatocytes (detox) + adrenal ctx (produces steroid hormones)

Golgi

   

Proteins/lipids ER  plasma membrane + vesicles Modifies N-oligos on nitrogen of asparagine Adds O-oligos on serine + threonine Add MANNOSE-6-phos for traffic to lysosomes FYI : I-CELL DISEASE – don't tag with mannose  secrete o enzymes OUTSIDE cell instead of lysosome  Coarse face, clouded corneas, corneas , restricted jts, jts, ↑↑plasma lysosomal enzymes  Fatal in chldhood

COPI 

ER  ER retrograde, Golgi  

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COPII 

anterograde, RERcis-Golgi

Endosome

outside or Golgi  lysosome or Golgi

Clathrin

Trans-Golgi  lysosomes , Plasma membrane  endosomes R-mediated endocytosis (forms coat)

Peroxisome

membrane-enclosed organelle for catabolism very LCFAs + AAs 

Proteosome

Proteins destined for peroxisome incorporation synthesized on free  polysomes  polysomes (ribosomes?)

= degradation damaged/unnecessary  proteins tagged by UBIQUITIN

Microtubule – Microtubule – general action, processes

-

Cilia (details below), flagella Mitotic spindle  Axonal trafficking Centrioles

*arranged with neg ( - ) end near centrosome (MTOC  ) + pos (+) radiates OUT 

Microtubules - dynein vs. kinesin

 Alpha + B-tubulin dimers, dimers, each with 2 GTP DYNEIN = RETROGRADE  (+  -) e.g. toward NUCLEUS = NEGATIVE

-

(hannahs home-made mnemonics – 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")  –retrograde")

KINESIN = ANTEROGR = ANTEROGRADE  ADE ( -  +) e.g. away from nucleus

-

Tubulin

Monomeric unites that comprise MT (necessary for movement cargo within cell )

Disease caused by defect in microtubule polymerization an d fusion of phagosome with lysosome

Chediak-Hagashi – MT polmerization defect  ↓↓ fusion phagosomes+lysosomes

Cilia structure

9+2 MT arrangement

  

Recurrent pyogenic infection Partial albino Peripheral neuropathy

Axonal dynein-ATPase  links peripheral 9 dblts  cilium bending Disease caused by immotile cilia (and cause of immotility )

KARTAGENERS  – immotile cilia d/t dynein arm defect     

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

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

Actin/Myosin – Actin/Myosin  – general actions

-

*Microvilli Muscle ctx Cytokinesis Adherens junctions

Location where processing "goes wrong" in cystic fi brosis

CFTR protein is misfolded in endoplasmic reticulum

DNA ligase

d/t ΔF508 mutation ( deletion phenylalanine )  interference folding + post-translational processing of oligosaccharide side chiains degraded by proteosome instead of membrane translocation

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

4

DNA Polymerase I

Read 3' 5' (e.g. start at OH grp and read to ward 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 g rp) Both polymerization NTs and processing/repair and processing/repair mechs

Polymerase III

Prokaryote only  Part of multiprotein complex, major replicating enzyme e. coli 

Topoisomerase and Abx

-

swivel points in DNA to relieve strain at replication (cut+reseal DNA)

Quinolones interfere here Cytosine deamination

= URACIL  if intact DNA repair mechanisms, these will be repaired (mismatch (mismatch repair genes will eliminate via base excision )

Dolichol

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? chains that will be transferred to protein component of  *N-linked carbohydrate chains albumin are assembled in RER + attached to colichol phosphate transferred

Arachidonic acid

to nitrogen of asparagine to form glycoproeins

secreted = albumin retained in membrane = insulin-R targeted to lysosome = hexosaminidase A (tay-sachs (tay-sachs))

Precursor of:

-

PGs Thromboxanes Leukotrienes

 phospholipase e A2 FA in phospholipid membrane released by  phospholipas Ceramide

Parent sphingolipid from 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) diseases)

Dermatan sulfate

GAG (glycosaminoglycan) -precursor of  proteoglycan  proteoglycan (carbs w/ small proteins  remember if protein>>carb component = glycoprotein) 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

Tetracycline

Binds ribosomal 30s subunit ( prokaryotic  prokaryotic small subunit  –  – euk = 40s)  prevents aminoacyl-tRNA attachment 

Aminoglycoside

Streptomycin, gentamycin, tobramycin, amikacin Inhibits eIFs = elongating initiation factors that help assemble 30s ribosomal  subunit with initiatior tRNA

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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 – site – incoming aminoacyl-tRNA P – growing polypeptide chain E = empty tRNA  AA has been transferred to growing molecule o n P site (exit )

Ribosome advances 3 NTs toward 3' end mRNA (e.g. toward end whose last NT  has free OH) OH)

Chloramphenicol

This moves peptidyl moves peptidyl RNA to P site = translocation

2 MOAs at 50S ribosome 1. 2.

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

RIBOZYME

RNA molecule that has catalyst  (E.g. enzymatic – "yme") – "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)

Hammerhead Ribozyme

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" – initiation" – it's a destruction rather than inhibition

Macrolides

Erythromycin, azithromycin, clarithro – static – static (Vs. cidal)

50S inhibitor  blocks translocation  – this uses GTP normally *(CHLORAMPHENICOL is also acting at 50S but blocking PEPTIDYLtransferase) PEPTIDYLtransferase) Clindamycin

Same as second MOA chloramphenicol –  chloramphenicol – block peptide bond formation at 50S ribosome

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

30S Aminoglycosides (Strepto, genta, tobra) – tobra) – bacteriocidal Tetracycline – etracycline – bacteriostatic 50S Chloramphenicol, Clindamycin – lindamycin – static Erythromycin (macrolide) – (macrolide) – static Lincomycin – incomycin – static Linezolid (variable static vs. cidal) **Linezolid **Linezolid is for VREs

post-translational modification collagen Mutation in early post-translational

Ehler-Danlos – Ehler-Danlos – skin + msk abnormalities

DNA methylation associated dz

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 = Down’s) MACROCHORDISM (big testes), long face, LARGE + everted ears, autism, MVP* (Fragile X = Xtra larges teses/jaws/ears)

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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 retardation - Type 1 – 1 – complete def., death in childhood  - Type 3 – 3 – partial  partial deficiency = deficiency = milder dz (pseudo-Hurler)  survives to adulthood

Incorrect splicing introns associated with what hematologic disorder

B-THALASSEMIA

Hematologic dz caused by missense pt mutation

HbS – Sickle cell Change A-->T at position 6 allows glutamine valine valine

-

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

HbC = modified version this error (glutamine (glutamine lysine) lysine)

Transition vs. transversion pt mutation

less serious and Asx if HbC/A but heterozygous HbS/C can act like HbSS and homozygote HbCC gives hemolytic anemia

Transition is substitution within same "class"  purinepurine / pyrpyr (same ring "type") Transversion = switch b/w purine/pyr (A-T

T-A or C-G )

(remember Purine – Purine – PURe As Gold = Glutamine, adenosine; pyrimidine – pyrimidine – CUT the PY = cytosine, thymidine, uracil in proks) Tautomerism switch point mutation

Switch single vs. double bond via bond via migration H+ Tautomers are isomers (structural isomers) isomers) of organic compounds that readily [1][2] interconvert by a chemical reaction called tautomerization. This reaction commonly results in the formal migration of a hydrogenatom or proton proton,, accompanied by a switch of a single bond and adjacent adjacentdouble bond. bond. The concept of tautomerizations 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 non-canonical base pairing in DNA and especially RNA molecules.

Significance of cytosine deamination

C  U  –  – 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 endonuclease sees newly formed Abasic site breaks PDE bond 2. DNA AP endonuclease 3. DNA Polymerase sees break and creates nick + 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 – epigenetics)) 5methylcytosine thymine + ammonia (MC single NT o mutation) – mutation) – corrected via thymine-DNA glycosylase – fixes cystine— cystine—thymine pt mutation in daughter cell  **Remember, thymine is a methylated uracil  so it makes o sense that CU would have methyl-CT

-

all others NOT recognized  Adeninehypoxanthine (this (this now prefers cytosine instead of  o thymidine) thymidine) o Guaninexanthine (this now prefers now prefers thymidine instead of  cytosine) cytosine)

*recall – *recall – deamination = removal of amino grp from molecule NT base with ketone

Guanine

NT base with methyl grp

Thymine

Alkylating agents

Cross-link guanine NTs in DNA damaging it enough to stop division Cisplatin Carboplatin

7

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) 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 (fluorouracil) – pyrimidine thymidylate synthase  Antipurine –  Antipurine – azathioprine (cleaved to 6-MP), thioguanine  Antifolate –  Antifolate – MTX (analogue that binds, inhibiting DHFR and formation THF), TMP, pyrimethamine, pemetrexed

DNA intercalating agent

Insert b/w 2 NT pairs  ΔDNA transcription/replication Fluorescent dye – Ethidium Bromide Cancer Rx – Rx – Doxorubicin, Daunorubicin Aflatoxin = Aspergi = Aspergillis llis Thalidomide  – teratogen with strict use policy for last resort anti-inflammatory  (leprosy) + salvage chemo in MM (With dexamethosone)



DNA cross-linking agents

Birth defect = PHOCOMELIA (horrible (horrible limb deformities as well as other body regions)

Form covalent bond b/w DNA NT bases –can't  –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/↑ wavelenth/↑energy vs. normal length  covalent adjacent thymine bond formed  THYMINE DIMER (r/o skin ca) Ionizing radiation – 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 break (MCC = CU

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) repair (hMSH/hMLH)

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Recombinational repair

One damaged strand has some replication – replication – use as template Nonhmologous end-joining (ALWAYS MUTAGENIC) – MUTAGENIC)  – DNA ligase complexes join separate ends dbl helix

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

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 enter RER in first place ( pre-folding  pre-folding error)

Lysosomes

Contain enzymes (made in RER) that degrade sugars (glycosidases) + proteins (proteases)

Intermediate filament stains – stains – vimentin

Connective tissue

Intermediate filament stains – stains – desmin

Muscle *note – connects – connects cytoplasmic bodies to membrane dense plaques in actin filament structure of smooth muscle; cardiac + skeletal myopathies associated w/  mutations in this protein

Intermediate filament stains – stains – cytokeratin

Epithelial cells

Intermediate filament stains – GFAP

neuroGLIAL cells – cells – astrocytoma, ependymal cells **REMEMBER **REMEMBER – GFAP – GFAP only marks astrocytomas, for prognosis use Ki-67

Intermediate filament stains – stains – neurofilaments

Neurons

Drugs that act on microtubules

Mebendazole/thiabendazole  – anti-helminth Griseofulvin  – anti-fungal Vincristine, Vinblastine  – anti-CA Paclitaxel  –  – anti-breast CA Colchicine  – anti-gout

Dynein arm defects

KARTAGENERS  – immotile cilia d/t dynein arm defect

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

Kinesin vs. Dynein



Male/female infertility



Bronchiectasis



Recurrent sinusitis



Situs inversus

Chediak-Hagashi – MT polmerization defect  ↓↓ fusion  phagosomes+ly  phago somes+lysosomes sosomes 

Recurrent pyogenic inection



Partial albino



Peripheral neuropathy

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

Make-up of microvilli

actin/myosin – actin/myosin – NOT microtubules

Actin, myosin, MT roles in replication

Actin/myosin = cytokinesis Microtubules = mitotic spindle, centrioles

Plasma membrane composition leading to decreased fluidity and higher melting temp

MORE cholesteroal  and/or MORE  long saturated FAs

RER activity + what cells have more

-

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)

SER activity + what cells



STEROID synth



DETOX rx, DETOX rx, poison



↑ hepatocytes (detox) + adrenal ctx (produces steroid hormones)

9

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) – (glycosides) – direct inhibit Na/K = indirect inhib indirect inhib Na/Ca (true target)  ↑[Ca2+]in = ↑contract

Na/K pump activation

Phosphorylated = ACTIVE  ATP ADP (donates phos)

Collagen types I – I – IV

" Be ( So T otally) otally) C ool, ool, Read Books I = Bone, Skin, tendon



Type ONE = BONE 

II = cartilage (with hyaline), vitreous body + nucleus pulposus



TWOlage Type TWO = car TWO

III = Reticulin = skin, vessels, uterus, fetal tissue, granulation tissue



Type III = ThreE D  defective in Ehlers-Danlos

IV = Basement membrane (Easy, think goodpastures)

 Disease a/w DEFECT in Type 1 collagen

"Four = Under the Floor "

Osteogenesis imperfecta ("BRITTLE BONE") – BONE") – COL1 A1/2 

The one that looks like child abuse



Multiple fx w/ minimal trauma

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BLUE SCLERA (translucent CT over choroid)

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Hearing loss (ABNL MIDDLE EAR BONE)

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DENTAL  lack dentin

*remember  I = Bone, Skin, tendon 

Type ONE = BONE 

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Disease a/w DEFECT in Type 3 collagen

Ehlers-Danlos – COL – COL3 A1  collagen + lysine hydroxylase gene mutations 

Hyperextensible skin



Easy BRUISING/Bleeds



Hypermobile jts

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

TYPE 4 (rare) = MENKE's dz (x-linked depigmented, lusterless KINKY hair with many facial/ocular/vascular/cerebral manigestations, copper LYSYL transport defect and ↓activity copper-depndent enzymes OXIDASE  –REMEMBER,  –REMEMBER, THIS IS CU-DEPENDENT ENZYME that crosslinks  pre-collagein in ECM to form mature collagen)

+/- associated with:



 Joint dislocation dislocation



BERRY ANEURYSM

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Organ rupture

*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 Syndrome (goodpasture = autoimmune not defect) 

hereditary GN



ESRD

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HEARING LOSS

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+/- ocular disturbances

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RECESSIVE (BOYS) MC type = X-LINKED RECESSIVE 

*remember  IV = Basement membrane (Easy, think goodpastures) Collagen – Collagen – 4 steps within fibroblasts + location

1.

2. 3.

4.

Collagen – Collagen – 2 steps outside fibroblasts

5. 6.

Implicated genetic defect in osteogenesis imperfecta

Synthesis (RER) RER) Translate alpha chains = PRE-PRO-collagen o Gly-X-Y o  X/Y = PROLINE, hydroxyproline/LYSINE  Hydroxylation (ER) ER) Of Proline + lysine residues  VITAMIN C CRITICAL o Glycosylation (ER) ER) o Of Pro-alpha -chain hydroxylysine residues + formation PROcollagen via H + DISULFIDE BONDS TRIPLE HELIX of 3 alpha chains o Exocytosis PROCOLLAGEN   extracell  o Proteolytic processing - CLEAVE terminal region = procollagenTROPOcollagen (insoluble) Cross-link - reinforce tropocollagen CROSS-LINKSb tropocollagen via covalent LYSINE-HYDROZYLYSINE CROSS-LINKSb (LYSIL OXIDASE)  FIBRILS

Type I collagen disorder ColA1, ColA2  unstable collagen triple helix not as strong (phenotypic outcome depends on unique changes in genes)

2 MC AAs in collagen

Glycine Proline Gly-X-Y  where X = proline (or lysin/glycine), Y = hydroxyproline)

Cartilage with PAS stain

Type III – III – Reticulin (skin, vessels , uterus, fetal tissue, granulation tissue)

Lysyl oxidase

Involved in forming collagen fibrils from pro-collagen triple helices that have been secreted into extracellular space *Copper-dependent Cross-linkage via covalently binding LYSINE —HYDROXYLISINE  Fibrils

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Cofactor requirement in early collagen synth

nd

VITAMIN C  –  – 2 step (HYDROXYLATION) within fibroblast in ER Without = SCURVY 

Elastin

Weakened vessels = ulcerated gums, tissue hemorrhage, anemia, ↓wound  healing, loose teeth, ↓bone formation

Stretchy protein in lungs, large arteries, elastic ligaments, vocal cords, ligamenta  flava (connect vertebrae for relaxed + stretched conformations) 

PROLINE, GLYCINE – NONglycosylated forms NONglycosylated forms



Tropoelastin w/ fibrillin scaffold

Disease MC a/w elastin defect

Marfans – fibrillin gene **FIBRILLIN = large ECM proteins a/w elastic + non-elastic microfibrils

Elastase and associated disease

Breaks down elastase – elastase – normally balance break down/build up but in alpha-1antitrypsin excess elastin = EMPHYSEMA (panacinar) + CIRRHOSIS/liver failure (#1 cause liver transplant in newborns!

Ddx uric acid + gout  primary reasons

Lesch-Nyan Alcoholism G6PD Hereditary fructose intoleranc intolerance e Galactose-1-P Galactose-1 -P uridyle transferase def . (severe galactosemia) galactosemia)  phosphorylated sugars sugars = **all disoders with increased accumulation of  phosphorylated ↑degradation products (e.g. AMP …uric acid)

Ddx uric acid + gout  secondary reasons

OVER-PRODUCTION Leukemia Myeloproliferative syndromes (MPDs) MM Hemolysis Neoplasia Psoriasis  Alcoholism UNDER-PRODUCTION Renal failure  ASA Diuretics  Alcohol (all  Alcohol (all 3 categories)

Direction DNA synthesis

5'3'

Direction RNA synthesis

5'3'

Direction DNA/RNA read

5'3' (e.g. mRNA is read 5'  3')

Protein synth

NC

Actinomycin D

Binds DNA, preventing RNA polymerase from moving along tem plate

Rifampin

Binds B-subunit RNA polymerase, inhibits initiation RNA synth

Interstitial deleting

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

Chromosomal inversion

Large large segment becomesreversed  becomes reversed w/i w/i same chromsome  rearrangement   post-breakage  post-breakage chr = chr = fusion oncogene

Ouabain

Binds K+ on Na/K pump, inhibiting Na/K ATPase

Digoxin/digitoxin

Cardiac glycosides Direct bind/inhibit Direct bind/inhibit Na/K ATPase  indirectly inhibiting Na/Ca exchange = ↑Ca in cell = ↑contractility 

Normal amount of an enzyme present yet no enzymatic

NONSENSE mutation – AA change generating 1 of 3 stop codons

activity – activity – where is mutation?



Three stop codons

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

mRNA is transcribed correctly transcribed correctly but during protein translation, would stop early (truncated, ineffective) ineffective)

12

Test for carrier genetic disease

PCR Amplify sequence of question and compare to normal

Steps in testing Lyme

ELISA first  –  – screening – screening – sensitive, rapid (can (can have false+) Follow-up with more specific WESTERN BLOT (protein)

Area where splice acceptor mutation occurs

3' end eukaryotic intron (invariant AG just before end  intron) intron) – HIGHLY CONSERVED 5' end intron = GT (GU in RNA) necessary  –  – splice donor site

snRNP

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 

discontinuous fragment = fragment  = SNP – SINGLE – SINGLE NT POLYMORPHISM) POLYMORPHISM) Location cleavage propetides collagen Cofactor required by phenylalanine hydroxylase

Extracellular  –  – first step; therefore is always "pro" type of collagen within cell

Tetrahydrobiopterin *Defect in either  PKU (MR, hypopigmentation…)

What "substance" crosses plasma membrane fastest?

CO2, followed by O2 then nitrogen, inhaled anesthetics etc.



diffusion is as rapid for these gases as it is for them in water



CO2 has higher solubility vs. water 

E-cadherin

 junctional complexes complexes (critical for formation and maintenance) Allows formation of  junctional 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 occludens + desmosomes desmosomes

Occludin

occludens tight junctions Transmembrane cadherin specific to zona occludens

Desmoglein

Transmembrane cadherin specific to desmosomes e.g. forms intercellular linkages at desmosomes which connect epithelial cells epithelial cells



PEMPHIGOUS VULGARIS – VULGARIS – anti-desmoglein Abs Irregularly shaped erosions in GINGIVAL, BUCCAL, palatine o mucosae POSITIVE Nikolsky test – test – apply pressure + epidermis appears o to separate from underlying dermis Bx: acantholysis w subsequent loss of cohesion o

Sites of synthesis proteins destined for lysosomal incorporation

RER

Bullous pemphigous vs. pemphigus vulgaris

Bullous = autoimmune IgG rxn vs. HEMIDESMOSOMES (collagen type XVII aspect) Pemphigous = DESMOGLEIN, tight junctions specific to epithelial cells, blisters, positive nikolsky, oral ulcers

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

 Alpha-1 agonists stimulate R on SM  ↑[Ca2+]in [Ca2+]in (IP3, DAG qiss – iss – Gq) 

vessels vs. muscarinic

contraction (constrict vessel ) Muscarinic can induce NO release (aka EDRF  –  – endo relaxing factor); produced  factor); produced   from arginine by endothelial cells

Muscle band changes during ctx – ctx – A, I, H

A = NO CHANGE I = shorten H = shorten (think –  think –  A  A is the best, so no need to improve, no need to Δ) A-spans width myosin thick  filaments (INCLUDING overlap actin thin)  length set by length of mysoin (thus noΔ @ctx) H = thick myosin WITHOUT overlap actin I = actin filaments ONLY  Z line – where actin filaments attach

13

MUST KNOW THIS – too easy to not  have on tip o tongue

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?

Mass solutes in cell don’t cell don’t change (while fluid volume does) Mass intracellular solute before = C1V1 Mass intracellular solute after = 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

Tx 

↑r/o all skin CA (1,000x↑ (1,000x↑)

1. retinoids - ↓CA but

↑incidence Japan

irreversible calcification tendons/ligaments - acitretin – treats keratoses, also used in psoriasis 2. 5-FU (pyramidine analog antimetabolite)

Cocakyn's syndrome

NER

AR

Bird-facies (thin nose, small head, large ears) Retinopathy, dwarf with long limbs, photosensitive Hyperpigment, erythema, teleangiectasias

No cure – supportive

*CS2 worse than 1

Premature aging Trichothiodystrophy

NER

AR

Sulfur Brittle hair/nails Fish skin – skin – scaly Physical/mental retardation

Rare, no cure

Fanconi's Anemia

ROS

AR 11 genes

BM fail w DNA repair defect - petechiase, bruise, pallor, café-au-lait  - infection, fatigue - aplastic anemia (pancytopenia), leukemia, solid tumors ( CA CA – liver, – liver, neck, esophagus, vulvar )

Tx symptoms (anemia/leukemia/CAs)

AR

↓growth w/ ↑r/o malignancy Butterfly facial telangiectatic erythema -resp/GI infection

AR

Aging, thin, tight, scleroderma-like skin ↓muscle, wrinkle, hyperkeratosis Cataracts, osteoporosis, arteriosclerosis, CA, DM  Japan, M=F 

DNA repair Cycle ctrl Bloom

Helicase Chr. Instab.

Werner's

Helicase (WS gene) gene)

First 10 yrs of life normal  death 40yo No tx

14

ATAXIA-TELANGIECTASIA

HNPCC/ LYNCH SYNDROME

BREAST CA

Chromos + chromatid breaks w rearrangmt

AR chr 7 + 14,  ATM gene **(= TCR + Ig regulation chr)**

Mismatch repair Microsat. Instability

AD MSH2, MLH1, (PMS2), Ras genes

Change in # of repeats of germline alleles accumulation mutations 80% r/o CRC Females have 30-50% r/o endometrial 

AD BRCA1

60-80% r/o serous adenoCAs

p53 DNA repair, cycle

Heterogenous, but marked by neurodegeneration (ataxia) + telangiectasia

Treat Sx Death teens

(2/2 dilation vessels) - sino-pulm infections ↑r/o CA, sensitive to xrays/radiation 

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

 pancreatic  BRCA 2 = ovarian , prostate , pancreatic 

GENETICS Blotting – Blotting – which for what

SNoW DRoP S = DNA N = RNA W = Protein Southwest = DNA-binding proteins (TF factors )

  Blot that allows determination of whether

This makes sense  DNA = South, TF=Protein = West Use labeled oligoNT probes

Northern blot

absence of protein is due to f ailure gene transcribed vs. post  vs.  post -transcriptional -transcriptional defect



Isolate RNA from PMNs  gel, blot, 32-P-DNA probe for specific gene

Technique used to separate false positive HIVELISA from true positives

Western blot

Uses DNA-DNA hybridization

Southern blot



Indirect geenetic testing within families, relatedness of individuals, determination epidemiologic relatedness of bacterial biotypes, e.g. strains S aureus producing TSS

Blot that gives semi-quantitave result for level of 

Northern blot

gene expression in tissue

15

Microarray use (for usmle at least)

( single NT polymorphisms) polymorphisms ) to study dz/tx SNP detection (single 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.

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% HIV  100% each Uses of FISH

( when deletion too small to see on Microdeletions at molecular level (when karyotype Fluorescent – Fluorescent – gene is present None = gene has been DELETED

Steps in production recombinant DNA (for



Isolate eukaryotic mRNA ( post-RNA  post-RNA processing) processing )

cloning)



Expose to reverse transcriptase

 

Insert cDNA into bacterial plasmid containing plasmid  containing antibiotic resistance genes

Conditional vs. constitutional transgenic mice

surviving bacteria

cDNA

on Ab medium produce cDNA library 

Conditional = targeted insertion/deletion targeted insertion/deletion gene via homologous

recombination Constitutive = random insertion gene into mouse genome RNAi

dsDNA made to separate + degrade target mRNA



Synthesized to complementary mRNA

When in mitosis do you stain for karyotyping?

Metaphase

Microsatellite instability

Characteristic with loss-of-function in mismatch repair genes (hMLH, hMSH  CA)) HNPCC , endometrial CA, ovarian CA, gastric CA 

Areas of diNT repeats a/w "slippage"  @replication  @replication that Δs number of  repeats on new strand (=instability) Mismatch repair genes would normally fix o

*Normal microsatellites can be 2-4bp totaling 1 effect on person's phenotype (sort of  opposite locus heterogeneity ) PKU causes many seemingly unrelated symptoms (MR hair/skin Δs ) OSTEOGENESIS IMPERFECTA (excess atypical fx, scoliosis, basilar skull deformities, blue sclerae, opalescent teeth, skin laxity)

Term - imprinting

Diff in phenotype depends on whether mutation is of  maternal vs. paternal  origin  – "happy puppet " PRADER-WILLI – Dad  – – hyperphagia + obesity  ANGELMAN'S – Mom – hyperphagia Chr15*

Term – Term – loss of heterogeneity

Patient inherits/develops mutation in tumor suppressor gene then the COMPLEMENTARY allele must be deleted/mutated BEFORE CA develops

RETINOBLASTOMA (Rb p100) Term – Term – Dominant negative mutation

Exerts DOMINANT EFFECT  heterozygote has non-functional altered protein that prevents normal gene product from functioning MUTATION of  TF in its ALLOSTERIC its ALLOSTERIC SITE   nonfunctioning mutant can still bind DNA thereby PREVENTING wild-type TF from bnding

Term – Term – linkage disequilibrium

Tendency for certain alleles to occur together more often than expected by chance 

Term - Mosaicism

Measured in  population NOT family + family + varies between different pops 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 LYONIZATION- random X inactivation in females DOWN'S trimsomy w/ mosaicism 47, +21 /46 -2-3% Down's, less severe

phenotype (↑IQ etc) – etc) – has half normal cells, half not  NON-disjunction chr21 occurs DURING MITOSIS NOT MEIOSIS in an early cell division) Term – 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) Term – Term – heteroplasmy

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 – Term – uniparental disomy

Offspring receives 2 copies chr from 1 parent and no copies from other

17

NONDISJUNCTION – meiosis 1 vs. 2

 paired chromosomes to separate + go to diff daughter  NONDISJUNCTION = failure = failure of  paired  cells leading to one daughter cell getting extra chromosome (n+1) while the other is 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  – SAME  EXACT chrosome passed to progeny  – 2 copies SAME EXACT  (e.g. 1 allele x2 from 1 parent and on e from other )

SUM if mom has alleles A+B, dad has C+D  if kid gets A, B, C = meiosis I  A,  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  reliable marker marker individual  individual  genetic exchange canNOT occur in this area and so probe = reliable chromosome Reciprocal vs. Robertsonian translocation

Reciprocal: true exchange DNA chrchr (fragments b/w chromosomes)  FUSION  GENE or CHANGE EXPRESSION existing gene 

BCR-ABL 9;22 CML

return"  of DNA (e.g. nonRobertsonian: large fragment 1 chr   another WITHOUT a " return"  nonrecipricol)  

3 DIFFERENT types Down's inheritance

1. 2.

3. Pedigree with horizontal transmission horizontal transmission

-

Robertsonian translocation (2114)

25% offspring 2 carrier parents affected, see in one generation only (usually) Commonly more severe than  AD disorders   shows up in childhood 

AD – 50% offspring affects, across generations

Pedigree x-linked recessive

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

AR – all effected are in same generation, e.g. unaffected parents but affected kids

-

Pedigree with vertical transmission vertical transmission

ACROCENTRIC CENTROMERES ( 13, 14, 15, 21, 22 o Minority DOWN's has 21 14 robertsonian (MCC Downs = trisomy )

Often PLEIOTROPIC , presenting after puberty 

FH crucial to dx 

zygous), but dad never passes on to his son (e.g. M > F ( female  female must be homozygous), male transmission) transmission ) NO male  male

-

50% sons to MOM CARRIER affected (heterozygoous mom)

Pedigree x-linked dominant 

*If DAD *If DAD is affected  ALL DAUGHTERS affected  *If MOM *If MOM is affected  Sons and daughters MAY be affected 

Example x-linked dominant

HYPOPHOSPHATEMIC RICKETS (formerly = vitamin-D-resistant rickets)

-

↑ phosphate wasting PROXIMAL TUBULE

rickets-like presentation  rickets-like 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 may have signs dz **often **often d/t  failure  failure oxidative phosphorylateion

Variable exprssion d/t heteroplasmy

-

MITOCHONDRIAL MYOPATHIES

LEBER’S HEREDITARY OPTIC NEUROPATHY  – acute loss of central vision MYOCLONIC EPILEPSY ENCEPHALOPATHY Y MITOCHONDRIAL ENCEPHALOPATH

-

"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, ½ 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

Possible if concomittant TURNER'S SYNDROME  (SHORT stature etc) since only 1X 

Hardy-weinberg

WILL SEE ABNORMAL KARYOTYPE – will see a missing sex chr 

2

2

p + 2pq + q =1 p+q=1 generally, given disease freq 2 (p ) or allele freq (p) freq, than if GIVEN disease freq, 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 p+q AND BE SURE to account for various  possible outcomes as you would with 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 DON’T know status 2 partner, use allele freq population as frequency  that gene in partner (almost 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 baby without knowing the other partner's status?

If frequency of dz = A,, then a = p

-

2

allelic frequency = √A  this will also be EQUAL TO frequency egg pA) 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 2

0.01= 0.01= p  p = 0.1

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 – they will not say "THIS IS  X-linked " so PAY   ATTENTION to the DISEASE BEING MENTIONED – do – do not go right to equation b/c it changes If x-linked  (  ish F or  or H annah's annah's GOLD H ockey  ockey Skills – bruton's – bruton's  x-linked = Boys W ish agammaglobulinemia, wiskot-aldrich, fabry's, hemophilia, G6PD, ocular  albimism, lesch-nyhan, duchennes(+beckers), hunters syndrome)

ASSUMPTION MADE IN H-W EQUATIONS

P=1

**DON’T **DON’T FORGET TO MULTIPLY BY 2 TO GET CARRIER FREQUENCY after  calculating q (carrier = 2pq and if p=1, carrier = 2q)

LINKAGE DISEQUILIBRIUM

Preferential association of allele at one locus with another allele at nearby locus more frequently than be chance alone

Genetic drift vs. gene flow

DRIFT – DRIFT  – gene frequency gene frequency Δ d/t  FINATE population size  – would ONLY SEE in small/closed communities FLOW – FLOW – gene exchange b/w different  populations  populations

20

WORKING THROUGH ALPHA-THAL genetics 27yo Asian-American 27yo Asian-American male comes to ED with RUQ abdominal pain 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 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 ( see separate "Chromosomal" table too )  ATM gene mutation

ATAXIA TELANGIECT TELANGIECTASIA ASIA (as name implies…) multiple dilated vessels + progressive ataxia Gene – 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

Excision endonuclease

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 – Defect – dimers persist

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 rings – corneal deposits -Kayser-Fleisher rings – 1.

DOWN's

TRISOMY 21 (47, +21) - MCC Trisomy MOSAICISM Trisomy  MOSAICISM 21 (47, + 21 / 46)  – 2-3% types  – normal cell line (46 chrs) a. 2 "populations" of cell types – nd  AND 2 line w/ trisomy 21 – 21 – ½ nl, ½ not  i. Less extreme phenotype (e.g. ↑IQ)

2.

NON-disjunction chr21 occurs DURING MITOSIS NOT  MEIOSIS in an early cell division) ROBERTSONIAN TRANSLOCATION (2114)

3.

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

Chromsomal disorders - specific chromosome chromosome locations

Disease

ChromOsome

Gene

Manifestations

CYSTIC FIBROSIS

7  AR

CFTR ΔF508 (phenylalanine delete)

Protein misfolded and improper oligosacch additions at endoplasmic reticulumproteasome (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

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)  function/activating)

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

**OTHER RET = hirschsprungs

PRADER-WILI VS. ANGELMAN

15q11

(deletion in area affected by imprinting )

Maternal deletion (With silent, methylated father allele) = Angel Mans (happy puppet) P aternal aternal deletion (silent/methylated mom allele) = P rader-Willi (MR, rader-Willi (MR, hyperphagia+obesity with initial poor feeding)

CRI-DU-CHAT

5q

microdeletion

High pitched monotonic cry  -

LI-FRAUMENI

 AD

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

Microcephaly, wide-set eyes, MR Epicanthial folds CARDIAC ABNORMALITIES , e.g. VSD

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

22

MICROSATELLITE INSTABILITY (2+)

 AD w/  variable  pene- pene trance

hLMH1 + hMSH2 mismatch repair genes

MC association = HNPCC but also in: -

Endometrial CA

-

Ovarian CA Gastric CA

DIGEORGE

22q11

*thymus  – structural/functional defect; missing  T-cell immunodeficiency  hypoparathyroid = 2° hyper calcemia calcemia *hypoparathyroid *craniofacial abnormalities, palate

SICKLE CELL

 AD

Glutamine valine valine @position 6 in Beta-globin gene

WILMS TUMOR

11p13

NEUROFIBROMAT

17  AD

Microdeletion

NF1 tumor-suppressor gene



Malignant urinary tract tumor



2/3 dx by 4yo



Surgical removal 

90% NF cases (vs. type 2) 

Multiple neurofibromas

TYPE 1 (VON



Café-au-lait



Lisch nodules – pigmented  – pigmented iris hamartomas

RECKLINGHAUSEN)



↑r/o pheochromocytom  pheochromocytoma a + mengingiomas mengingiomas

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BILATERAL acoustic neuromas (schwanomas is tip-off) – tip-off) – otherwise, the rest are both NF1/2:

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Neurofibromas

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Café-au-lait

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↑r/o meningioma+pheo

FBN1 – fibrillin 1

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Marfinoid habitus – habitus – tall, hyperextensible, pectus excavatum + kyphoscoliosis

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

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Subluxation lens

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Heart defects Cystic Medial Necrosis of aorta o o Dissecting AA Valvular insufficiency  –  – Mitral regurg = holosystolic murmur  o in apex  MVP = midsystolic click ) o

VHL = t umor umor suppressor gene

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Hemangioblastomas CNS + RETINA

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RENAL CELL CA

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Cysts internal organs

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Sebaceous adenomas (Angiofibromas of sebaceous glands) Subependymal nodules = LISCH NODULES o

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Epilepsy

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MR



dysplastic white matter lesions = Hamartomatous lesions skin, CNS, viscera

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Cortical tubers

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Shahreen patches (see picture -- -- --- ---

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 Ash-leaf spot (hypomelanic, light patches, Wood's)

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RENAL ANGIOMYOLIPOMAS

OSIS

NEUROFIBROMAT OSIS

22  AD

NF2 tumor suppressor gene

TYPE 2

MARFAN

VON HIPPELLINDAU (VHL) TUBEROUS SCLEROSIS

15  AD

3  AD

 AD

TS 1/2



Heart Defect RHABDOMYOMAS

23

OSTEOGENESIS IMPERFECTA

("BRITTLE  ("BRITTLE  BONE" )

7 or 17 - locus heterogeneity   AD

COL1A1/2 – type 1 procollagen

**PLEIOTROPY ** ** - blue sclerae seemingly unrelated to fx **LOCUS OF HETEROGENEITY  HETEROGENEITY ** ** 2 diff single chromosome mutationssame dz

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Looks like child abuse  Multiple fx w/ minimal trauma

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BLUE SCLERA (translucent CT over choroid)

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Hearing loss (ABNL MIDDLE EAR BONE)

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DENTAL

 lack dentin

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

EHLERS-DANLOS

 AD and   AR – many types

COL3A Type 3 collagen

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Hyperextensible skin

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Easy BRUISING/Bleeds

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Hypermobile jts

**6 **6 types w/ varying inheritance/severity (AD or AR) +/- a/w: 

 Joint dislocation dislocation

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BERRY ANEURYSM



Organ rupture

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

Heterogenous, but marked by neurodegeneration (ataxia) +

ATAXIATELANGIECTASIA

ChroAR mos + chr 7 + 14, ATM 14, ATM ( PI3 PI3 kinase) chrom- that phosphorylate >700  proteins in DNA repair * inc. atid breaks p53 + BRCA-1 tumor supp ( chrs correspond to = TCR + Ig w/ reg)** rearra ngmt

(WERNERS )

 AR

WS gene

FANCONI

 AR

11 genes  DNA repair, ROS vulnerability, Cell cycle dysregulation

BM fail w DNA repair defect - petechiase, bruise, pallor, café-au-lait  - infection, fatigue - aplastic anemia (pancytopenia), leukemia, solid tumors ( CA – liver, – liver, neck, esophagus, vulvar ) - Tx symptoms (anemia/leukemia, etc)

XERODERMA

 AR

Excision endonuclease – endonuclease – thymine dimer repair 

UV light sens  freckles, skin CA (1,000x↑ (1,000x↑) , corneal ulcerations

PIGMENTOSUM



helicase error

telangiectasia (2/2 dilation vessels) - sino-pulm infections ↑r/o CA, sensitive to xrays/radiation

Aging, thin, tight, scleroderma-like skin ↓muscle, wrinkle, hyperkeratosis Cataracts, osteoporosis, arteriosclerosis, CA, DM  Japan, M=F 

↑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 – Defect – dimers persist

BREAST CA

 AD

BRCA 1 (2 = ovarian/ prostate/ pancreatic)

ALS

 AD

SOD1 – copper/zinc superoxide dismutase

60-80% r/o serous adenoCAs

24

MENKE'S (TYPE 4 TYPE 4 E HLERS HLERSD ANLOS )

 Xlinked 

 ATP7A – ATP-dependent copper transport protein

Ehlers-Danlos Ehlers-Danlos type 4 – "collagen" 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 (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

SICKLE CELL

4  AD

CAG triNT repeat 

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Depression

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Progressive dementia



Choreiform

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CAUDATE ATROPHY 



↓GABA + ACh in brain



20-50yo

 AR  APC - tumor suppressor gene

FAMILIAL ADENOMATOUS POLYPOSIS

RETINOBLASTOMA

 AD w/  variable  pene- pene trance

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

WILLIAM'S

7q

El asti  asti n (microdeletion)

Elfin facies, HYPER-Ca 2/2 ↑sensitivity to sensitivity to vitD), good verbal, good verbal, very friendly, very  friendly, heart issues

ACHONDROPLASIA

3  AD

FGF-R3 - cell signaling defect

Dwarf, short limbs, but normal head/trunk size **a/w advanced paternal age

FAP

5  AD

 APC  –  – deletion

- >puberty, colon covered with polyps - CRC always CRC always if not resected /(usually ~40yo)

DUCHENNE'S MUSCULAR DYSTRPHY VS. BECKER' S

 Xlinked 

Dystrophin

DUCHENNE = frame-shift = DELETION dystrophin gene  accelerated muscle breakdown

DISEASE

 – LARGE DELETION single gene vs.  pt mutation same gene

2+

- Onset