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CELL MEMBRANE DISORDERS

 Acanthocytosis/Spur Cell Anemia:

o Too much alcohol or cholesterol  extra cholesterol accumulate in outer leaflet
 increases surface area of outer bilayer  Less deformable  thorny  RBC
destroyed by spleen  anemia
o Destruction of liver à can’t produce albumin anymore à albumin usually keeps
fluids in the bloods. Can’t keep fluid in the blood anymore, and fluid seeps out
into peritoneal cavity à ascites

 Glanzmann’s Thrombasthenia:
o Autosomal recessive
o Missing glycoprotein IIb or IIIa (“glue”)  platelets can’t stick together 
hemophilia

 Malaria:
o Plasmodium falciparum attacks Glycophorin A  cells adhese  anemia,
hepatosplenomegaly, ischemia.

 Hereditary Spherocytosis
o Autosomal dominant
o Non-functional spectrin, ankyrin, or protein 4.1  RBCs become round 
anemia, jaundice, splenomegaly.
o Tx: folate, splenectomy.

 A possible cancer treatment is to attack tumor glycocalyx

 Liposomes can be used for Drug Delivery – 3 components needed within the liposome:
o Drug (either hydrophilic, or lipid-soluble)
o Antibody (homing peptide) to bring the entire liposome to the antigen
o PEG – protect from phagocytes.

MITOCHONDRIAL DISORDERS

 Barth Syndrome (x-linked): cardiolipin synthesis defect  inner membrane of

mitochondria defective  H+ leak out more easily  less ATP made  muscle
weakness, cardiomyopathy, neutropenia, mitochondrial cristae squished together

 Bcl-2 proteins (BAD, BAX) in cytosol  poke hole in mitochondria (MPTP)  cyt c
leaks out  apoptosome forms  caspase cascade  apoptosis

 mtDNA vs nuclear DNA

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o Mito imports: RNA polymerase, amino acids, mitochondrial DNA replication

enzymes, mitochondrial aminoacyl-tRNA synthases, and mitochondrial ribosomal
proteins
o Mito makes its own: rRNA subunits, tRNA

 Hsp70 and signal translocation sequence target protein to TOM  TIM  signal
sequence cleaved  hsp60 help fold the rest inside mito.

 SOD2 vs. GPX

o SOD2 before peroxide step, GPX after peroxide step.
o Similar to Oxidase (before) and Catalase (after) in Peroxisome

MITOCHONDRIAL GENETIC DISORDERS

 PEO (progressive external ophthalmoplegia)(autosomal dominant): mutation in

POLG2 (Pol Gamma) or TWINKLE (mt helicase)  ptosis, weak eye muscles

 Alpers Syndrome (autosomal recessive): no pol gamma  less mtDNA made  mental
deterioration, seizure, blind, deaf, death

 Kearns-Sayre Syndrome (KSS) – giant deletions of mtDNA in muscles (heart, eyes)

 Pearson Syndrome – KSS + bone marrow derivatives  pancytopenia (decrease in all

blood cells), sideroblastic anemia

 MELAS (Mitochondrial Encephalomyopathy Lactic Acidosis Stroke-Like Episodes)

(maternally-transmitted): mutated tRNA-Leu  can’t make proper mitochondrial
proteins.

 MERRF (Myoclonus Epilepsy and Ragged Red Fibers)(maternally transmitted):

mutated tRNA-Lys  can’t make proper mitochondrial proteins.

 LHON (Leber’s Hereditary Optic Neuropathy): missense mutation of Complex I in

optic nerve  blindness, occur more in males (because only have one X chrom)

 NARP (Neurogenic Muscle Weakness, Ataxia (lack of muscle coordination),

Retinitis Pigmentosa): mutated ATPase 6 gene  retinitis pigmentosa

 Leigh Syndrome: more severe form of NARP. Accumulated mutations over generations.

 Mitochondrial Diseases Summary

o Diseases involved in deleted nuclear DNA that goes into mito (Alpers, PEO) –
only one that’s not maternally transmitted)
o Diseases involved in deleted parts of mtDNA (KSS, Pearsons)

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o Diseases involved in mutations in tRNA genes (i.e. MELAS, MERFF)

o Diseases involved in protein coding nuclear genes (i.e. LHON, NARP, Leigh)

NUCLEAR DISORDERS

 Phosphorylation vs. Dephosphorylation of lamin

o Phosphorylation disassembles lamin (by cdk1 during prophase)
o Dephosphorylation assembles lamin

 Emery-Dreifuss Muscular Dystrophy: mutated lamin A/C (autosomal) or Emerin (x-

linked)  chromatin goes into cytoplasm  muscle weakness, arrhythmias, can’t flex
elbows and neck well.

 Dilated Cardiomyopathy: mutated lamin A/C  congestive heart failure

 Lipodystrophy: mutated lamin A/C  pre-Lamin A interact with adipocyte TF 

impairs adipocyte differentiation  fat neck and face, thin body, diabetes

 Autosomal Dominant Leukodystrophy (ADLD): Lamin B Duplication 

demyelination of CNS MS

 Hutchinson-Gilford Progeria: mutated lamin A  unstable nuclear envelope, bleb,

NPC clustering  nuclear damage  cells die fast  accelerated aging.

 Lamin A binds to :
o Architectural partners
o Chromatin partners
o Gene-regulatory partners
o Signalling partners

 snRNP vs. snoRNP

o snRNP used in slicing
o snoRNP used in rRNA assembly

 Spinal Muscular Atrophy: mutated SMN (in gems)  can’t make snRNP right 
can’tsplice  lose motor neurons  muscle atrophy

 PARTS OF THE NUCLEOLUS

o Fibrillar Center – inactive DNA (has “fibrils” of DNA)
o Dense fibrillar components (pars fibrosa) – active DNA (dense because you also
got rRNAs here and snoRNPs)
o Granular Component (pars granulosa) – maturing ribosomal precursor particles
here (ribosomal subunits look like “granules”)

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ER/GOLGI DISORDERS

 Angelman Syndrome: mutation chrom 15 for ubiquitin ligase (only maternal active, while
father’s is imprinted)  can’t polyubiquinate stuff for degradation happy baby,
epilepsies, jerkiness.

 Cystic Fibrosis: mutation in CTFR (Cl ion channel), class 2 mutation (Cl ion channel not
folded properly)  rhonchi, crackles in lungs, bronchiectasis (find Cl- in sweat test)

 Familial Hypercholesterolemia: defective LDL-R (doesn’t make it to membrane)(class

II) LDL can’t be taken up from the plasma (blood) so stay in circulation à premature
atherosclerosis, corneal arcus, xanthomata (cholesterol lumps in tendons), xanthelasmata
(cholesterol lumps under skin)

 Creutzfeld Jacob Disease: GPI-link’s alpha helix becomes beta sheet  prion 
accumulates  shrink brain.

 Cell Disease: GlcNac Phosphotransferase is deficient, so M6P tag is COMPLETELY

missing! (remember M6P tag usually added in cis-Golgi) acid hydrolases don’t go to
lysosome  waste products accumulate in cells as inclusion bodies lack of growth,
psychomotor retardation, death CHF.

EXOCYTOSIS DISORDERS

 Botulin Toxin: synaptobrevin cleaved  Ach can’t fuse at NMJ  flaccid paralysis

 Tetanospasmin: synaptobrevin cleaved  GABA/Gly (inhibitory NT) can’t fuse at NMJ

 spastic paralysis

 Direct vs. Indirect Pathway

o Direct Pathway = protein Golgi directly to the apical/basolateral side of plasma
membrane
o Indirect Pathway = protein goes from golgi to some random side, then gets sorted
to apical/basolateral later.
o Transcytosis is indirect pathway!

ENDOCYTOSIS DISORDERS

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 Pinocytosis = only one that all cells do (constitutive); remodeling of cytoskeleton;

vesicles travel via microtubules.

 TB: macrophage swallows TB  TB prevents phagolysosome formation by interfering

with Rab (phagosome can’t fuse with lysosome for digestion) hemoptysis (coughing
blood), chest pain, fever

 Clathrin used in exocytosis and receptor-mediated endocytosis (remember not in

phagocytosis or pinocytosis)

 Legionnaire’s Disease: spread by aerosol  spreads through lungs.

 Familial Hypercholesterolemia:
o I: can’t make LDL-R
o II: makes LDL-R, but can’t transfer to the plasma membrane
o III: LDL-R makes it to the plasma membrane, but LDL cannot bind to it.
o IV: LDL can bind to LDL-R, but it can’t cluster to form coated pits for vesicle
budding (because coated-pit binding site defective).
o V: You form vesicles, but the LDL-R’s cannot be recycled

LYSOSOME DISORDERS

 M6P Tag is put on in Cis-Golgi by GlcNAc phosphotransferase. Mnemonic: M-“cis”-P

 V-Type ATPase maintains H+ content inside lysosome so Acid Hydrolases can stay
active.
 Lysosomal membrane lipids & proteins are heavily glycosylated to protect them from
digestion

 Polyubiquitination vs. Monoubiquitination

o Polyubiquitination is used for proteins that are made in the cell to go to
proteasome.
o Monoubiquitination is used for proteins that are endocytosed from outside the cell
to go to lysosome.

 Mucopolysaccharidoses vs. Sphingolipidoses vs. Mucolipidoses

o Mucopolysaccharidoses – accumulate GAG
o Sphingolipidoses – accumulate sphingolipid
o Mucolipidoses – accumulate glycoprotein and glycolipid

 Melanosome = specialized lysosome

 Cell Disease (Mucolipidosis II): GlcNac Phosphotransferase is deficient, so M6P tag is

COMPLETELY missing!  acid hydrolases don’t go to lysosome but accumulate
extracellularly as inclusion bodies lack of growth, psychomotor retardation, death
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CHF.
 Pseudo-Hurler Polydystrophy (Mucolipidosis III): Milder I-Cell Disease, later onset

 Gaucher’s Disease: most common lysosomal storage disease. Deficiency of

glucocerebrosidase → accumulation of glucocerebroside (a glycosphingolipid) in
macrophages = Gaucher’s cells  hepatomegaly & splenomegaly, Hypersplenism,
anaemia, neutropenia & thrombocytopenia
o Type II has Hypertonia = inability of muscle to stretch. Also MR,
o Type III has Myoclonus = twitching of muscles
o Erlenmeyer flask deformity of distal femur

 Hurler’s Syndrome: most severe MPS. Deficiency of α-L-iduronidase → accumulation of

dermatan sulphate & heparan sulphate (GAGs)  Physical & mental deterioration,
hirsutism, deafness, AND CORNEAL CLOUDING!!!

 Hunter’s Syndrome: just like Hurler’s syndrome except missing iduronodate sulphatase
and NO CORNEAL CLOUDING and is X-LINKED!!!!
:
 Sanfilippo syndrome (MPS III): like Hurler’s except kids live longer and severe behavior
problem

 Morquio syndrome (MPS IV): Normal IQ. Accumulate keratan sulphate.

 Chediak-Higashi Syndrome: Mutation CHS1/LYST (gene for lysosomal trafficking

regulatory protein). Vesicles can’t walk on microtubules to get to lysosomes properly 
Delayed fusion of phagosome with lysosome in leukocytes
o Side Effect: Autophagocytosis of melanosomes in melanocytes → albinism
o Granular defects in NK cells & platelets

PEROXISOMAL DISORDERS

 Oxidase vs. Catalase

o Oxidases used to make H2O2
o Catalase use H2O2 to oxidise toxins

 Catalase in peroxisome and GPX in mito do the same thing.

 β-oxidation of very long chain fatty acids (VLCFA)

o VLCFA (≥ C24) can only be degraded in peroxisome

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o Initiated in peroxisome until C10, completed in mitochondria

o Energy released as heat
o Fatty acid oxidation = Major source of metabolic energy
o Fatty acids → AcetylCoA → cytosol;
o used for biosynthesis of cholesterol & bile acids

 Nucleic acid purines (A, G) = degraded to uric acid then urate by Xanthine oxidase 
excreted

 Gout: a lot of xanthine oxidase activity  lotta purines converted to uric acid
(hyperurecemia) (too much uric acid)  arthritis. Tx: Allopurinol (xanthine oxidase
inhibitor)
o Humans don’t have uric acid oxidase in our peroxisomes à eat too much purines
à Gout

 Zellweger Syndrome: peroxins stop recognizes SKL can’t import peroxisomal

enzymes  liver failure (because trying to filter all the junk), muscle weakness (because
bile acids can’t be producedlipids not digestedless ATP), VLCFA accumulate in
blood and tissues, hypomyelination (because can’t make plasmologen), Big Forehead!

 XALD (X-Linked Adrenoleukodystrophy): most common peroxisomal disorder.

Can’t transport VLCFA into peroxisome  VLCFA accumulate in brain (myelin
breakdown) and adrenal cortex (adrenal atrophy) apathy, ataxia

 Plasmalogens (made in peroxisome) are the most abundant phospholipids in myelin. The
products of VLCFA beta oxidation are used for biosynthesis of cholesterol, bile acids,
and other compounds.

 Zellweger vs. XALD

o Zellweger = peroxisome can’t import peroxisomal enzymes
o XALD = peroxisome can’t import VLCFA

SIGNAL TRANSDUCTION DISORDERS

 Cholera Toxin: keeps Gs in active state  too much cAMP made  prolonged
stimulation  too much Cl and Na transported across membrane  water follows salt 
diarrhea

 Pertussis Toxin: blocks Gi  Gi inhibited  too much cAMP  prolonged stimulation

 Retinitis Pigmentosa 4: mutated rhodopsin  GPCR defective lose peripheral vision

(because rods here). Tx – Vitamin A slows down process.

 G-Proteins (and what they’re involved in):

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o Ran = nuclear translocation

o Arf = vesicle budding
o Rab = vesicle fusion
o Ras = signal transduction (as in GRB2-Sos-Ras)
o Rho = actin polymerisation – stress fibers
o Rac = actin polymerisation – lamellipodia
o Cdc42 = actin polymerisation - filipodia

 NIDDM (Non-Insulin-Dependent Diabetes Mellitus): Obesity  insulin receptor

defect  no PI3K(effector)  no PIP2 to PIP3 (2nd messenger)  no PKB activation 
GLUT4 vesicles cannot fuse with Plasma Membrane  hyperglycemia  affects eyes,
muscles, blood vessels, liver, kidney.

 RTK Signalling Defects:

o VEGF – Colorectal cancer, NSCLC
o EGFR (HER1)  Breast Cancer, Colorectal Cancer
o EGFR2 (HER2)  Breast Cancer

 G-PROTEIN RECEPTORS
o Gs, Gi: effector = adenyl cyclase, 2nd messenger= cAMP , activates = PKA
o Gq: effector = PLC, 2nd messenger= DAG/IP3, activates = PKC

 RTK RECEPTORS
o RTK - PLC: eff = PLC, 2nd = DAG/IP3, activates = PKC
o RTK – PI3K: eff = PI3K, 2nd = PIP2/3, activates PKB (i.e. AKT/PTEN)
 (PI3K: PIP2àPIP3 whereas PTEN: PIP3àPIP2 )
 (AKT is like PKB)
 Insulin signalling uses the PI3K-PKB pathway à effect vesicles with Glut4
receptors to merge with PM
o RTK – GRB2-SOS-Ras-MapK-TF(Fos/Jun)-GF Pathway

 NON-TK RECEPTORS
o Cytokine Receptors: 1st messenger= cytokine, Eff=JAK Phosph’d à STAT
Phosph’d àSTAT dimerized à transcription
o Integrin receptors: 1st messenger=collagen à Eff=ILK (integrin-linked kinase) or
FAK (focal adhesion kinase) àprolif, growth, differentiation, apoptosis

 SERINE-THREONINE KINASE RECEPTOR

o Serine-Threonine Kinase Receptor: 1st messenger=TGFbeta à Eff=S/T domain
à 2nd messenger à Smad2 or Smad3 dimerase with Smad4 à transcription

 INTRACELLULAR RECEPTORS

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o Steroid Hormone Receptors: Steroid and Zinc  Receptor  HRE 

transcription
o NO Receptors: Acetylecholine NO synthase  make NO from arginine  NO
then goes to smooth muscle cell to convert GTP to cGMP, which relaxes it.

MICROTUBULES DISORDERS

 MTOC = place where microtubules grow from… so find in migrating cells, mitotic cells,
nerve cells, base of cilia and flagella, etc.
o gamma-tubulin rings in MTOC "seed" sphere
o Basal bodies = MTOCs under cilia and flagella

 Dynactin complex attach dynein or kinesin to vesicle.

 Viruses can travel on dynein (+-) or kinesin(-+) to and fro cell body.

 Varicella Zoster Virus: Virus in dorsal root ganglion travel via kinesin to end of nerves
at skin. “Chicken Pox”, “Shingles”

 Rabies: Virus can travel from wound via dynein to CNSencephalitis  prodromal
phase (headache, malaise)neuro phase (delirium)coma death (respiratory failure)

 MAP vs. Kinesin13

o MAP (microtubule associated protein) stabilizes microtubules. i.e. tau
o Kinesin 13 (catastrophe factor) destabilizes microtubules

 Alzheimer’s Disease: hyperphosphorylated tau  MT tangles  Neurofillamentary

tangles + beta amyloid plaques accumulate. Diagnose: increased tau in CSF. Also see in
trisomy 21

 Huntington’s Disease: Hungtingtin mutated (CAG repeats at N-terminal) MT

destabilize  accumulate in brain, adhese transcription factors neuronal cell death 
chorea (jerkiness), dementia, forgetfulness, death

 Familial Motor Neuron Disease (MND): mutation in Dynactin subunit  lower motor
neurons (musc atrophy, weakness), or upper motor neuron (hyperreflexia)

 Familial Amyotrophic Lateral Sclerosis (ALS): mutation in SOD1 lower motor

neurons (musc atrophy, weakness), upper motor neuron (hyperreflexia)

 Chediak-Higashi Syndrome: USMLE says it’s a microtubule problem when it really is

a lysosomal trafficking problem  lysosome don’t fuse with phagosomes on time in
leukocytes. Autophagocytosis of melanosomes  albinism

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 Notice you have 2 inner and 3 outer dynein arms in cilia.

 Primary Cilia Dyskinesia: Lack/Defective inner dynein arm  Immobile cilia  sperm
can’t swim, fallopian tube can’t carry ovum, and you get bronchitis, otitis media, and
sinusitis. Kartagener Syndrome

 TX:
o Colchicine: inhibit polymerization of MT  Cell Death. Treat Gout
o Vincristine/Vinblastine: inhibit polymerization of MT  Cell Death. Treat
cancers w/ high mitotic index
o Paclitaxel (Taxol): inhibit depolymerization  blocks mitosis  Cell Death.
Treat breast, prostate, lung cancer. ODDBALL (only one that inhibits
depolymerization).

INTERMEDIATE FILAMENT DISORDERS

 MT vs. IF vs. Actin in assembly energy

o MT: need GTP to assemble
o IF: don’t need GTP or ATP to assemble
o Actin: need ATP to assemble

 Epidermolysis Bullosa Simplex (EBS): Rupture of Keratin in cells connected to Basal

layer (mutation in Keratin 5 and 14)  blisters (i.e. soon after birth)

 Epidermolytic Hyperkeratosis (EH): Mutation in Keratins 1 and 10 keratin

proliferates  thickened skin, easy blistering, infections

 Epidermolytic Plantopalmar Keratoderma (EPPK): Mutation in Keratin 9 (outermost

keratinized layer of epidermis)(only in sole and palm) treebark on hands and feet

 Desmin Related Myopathy: desmin mutation  desmin aggregates throughout cell 

muscles become disorganized  muscle cell apoptosis  muscle weakness, atrophy,
cardiac and respiratory failure

 Neurofilament defects found in Alzheimer’s, Parkinson’s, and ALS (amyotrophic lateral

sclerosis)

 Different Types of Tangles:

o Glial Tangles = tangles of GFAP
o Lewy Bodies = tangles of neurofilament
o Neurofibrilary Tangles = hyperphosphorylated tau in AD (mitochondria!)

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ACTIN DISORDERS

 MT vs Actin
o MT: + end = grow; - end = breakdown
o Actin: + end = fast grow; - end = slow grow

 Notice that ATP is in g-actin. ADP is in f-actin

 “Seeds”
o MT seed: tubulin gamma
o Seed for branched actin: ARP (actin-related protein) (- end)
o Seed for unbranched actin: Formin (+ end)

 Profilin exchanges ADP for ATP on the G-actin, making it ready for polymerization.

 High vs. Low concentration of ATP-G-Actin

o High conc ATP-G-Actin: monomers added at both ends, but faster at +
o Low conc ATP-G-Actin: monomers added to + and come off - à treadmilling

 TYPES OF ARFs!!
o ARFs that bind to G-actin
 Thymosin: binds G-actinà prevents F-actin assembly (“thanatopsis”)
 Profilin: Binds G-actin à promotes F-actin assembly (“promotes
filament”)
o ARFs that bind to F-actin
 Cofilin: disassemble at – end (disassemble) (“cuts filament”)
 Gelsolin: caps + end (prevent further growth) (“gel sol cap”)

 Besides being in muscles, actin are in:

o Microvilli – they just are.
o Stress Fibers – contractile bundles of actin
o Lamellipodia/Filipodia – contract to move cell
o Cytokinesis – contract to pinch cells apart

 Two types of cross-linking:

o To form parallel cables (“bundles”) –
 alpha actinin (contractile, because loose so myosin can insert in it, i.e.
stress fibers),
 fimbrin (non-contractile, because dense, i.e. microvilli), villin
o To form filament webs (“gel”) –
 spectrin (remember in RBC),
 filamin (“filament”)

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 Stress fibers (remember they are contractile, so they are crosslinked by alpha-actinin)
connect to ECM via focal adhesions (integrin). Remember they are used in cell signaling
(collagen effect integrin àeffect ILK or FAK à proliferation)

 Stress fibers vs. Microvilli

o Stress fibers: alpha-actinin and focal adhesions cross-linking/attaching actins to
integrins (in ECM)
o Microvilli: Fimbrin and Villin cross-linking actins

 G-Proteins: Rho vs Rac vs Cdc42

o Rho = actin polymerisation (via formin “unbranched cables”) – stress fibers
o Rac = actin polymerisation (via WASP then arp2/3 because branched) –
lamellipodia
o Cdc42 = actin polymerisation (via WASP then arp 2/3 because branched) –
filipodia
o Mnemonic: “Rhostress,” “Raclam,” Cd. Fili”

 Wiscott-Aldrich Syndrome: Defective WASP  no Arp2/3 activation  no actin

nucleation  no lamellipodia or filipodia  defective signaling pathway (notice
acronym almost like “WASP”)

 Drugs that Affect Actin Polymerisation:

o Cytochalasin D: bind to + end, ends polymerization, depolymerisation at – end
o Latrunculin: like sponge – soaks up free monomers, prevent polymerization
o Phalloidin: binds to filament, stops polymerization. Remember Red Texas
Phalloidin?

 Myosin:
o I has I head + calmodulin (“I” looks like a microvilli)
o II has II heads + essential + regulatory – II looks like squeezing (contractile)
o V has 2 heads + calmodulin (V for Vesicle!)

 Proteins that attach to Actin/Myosin

o Cap Z = cap at the Z disc
o Titin = pulls myosin tight
o Tropomodulin = “tropo minus end”

 CapZ vs. Tropomodulin

o CapZ @ + end
o Tropomodulin @ - end

 Z disc = CapZ + alpha-actinin

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 Mechanism for Muscle Contraction

o ATP-binding detaches myosin head (the reasoning behind rigor mortis)
o ATPàADP moves it into the myosin-binding site
o ADP-detachment does powerstroke

 Dilated Cardiomyopathy: besides mutation in lamin A/C, can also be caused by

mutation where actin binds Z disc.

 Familial Hypertrophic Cardiomyopathy: mutation in myosin II  #1 cause of

suddencardiac death in athletes!! Just randomly drop dead. Muscular heart with large
atrium andsmall ventricle.

MUSCULAR DISORDERS

 Actin - dystrophin – (beta dystroglycan-GRB2-alpha dystroglycan) - laminin2

 Satellite Cell (in basal lamina of mature muscle) à myoblast à +myotube +myofibers à
mature muscle
 Stem Cell “Side Population Cells” (in bone marrow) à differentiate into satellite cells

 Muscular Dystrophy à repair cannot keep up with damage à connective tissue + fat
accumulation. Detect w/ blood test – find increased serum creatine kinase. Or do PCR
deletion screening.

 Absence of dystrophin → loss of DAP (dystrophin associated proteins) at

sarcolemmaAbsence of physical link → fragile sarcolemma

 Dystrophin = largest gene therefore prone to many mutations. Binds actin cytoskeleton to
sarcoglycan-dystroglycan complex.
 X-LINKED MUSCULAR DYSTROPHIES:

o Duchenne’s Muscular Dystrophy: X-linked or gonadal mosaic à TOTAL loss

of function of dystrophin  Gower’s Maneuver, calf pseudohypertrophy (calf
looks big and muscular but its not, because damage accumulates a lot of fat and
connective tissue), mild cognitive impairment, death by cardiac/resp failure. 8%
of female carriers of DMD gene have partial weakness. Called MANIFESTING
HETEROZYGOTES.

o Becker’s Muscular Dystrophy: like DMD but PARTIALLY functioning

dystrophin (rather than TOTAL loss of function in dystrophin).

o Emery-Dreifuss: mutation in A/C or Emerin  early contractures (shortening of

muscle, can’t stretch)  cardiomyopathy and arrhythmia.

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 AUTOSOMAL MUSCULAR DYSTROPHIES:

o Myotonic Muscular Dystrophy: Accumulated CTG repeats (1000’s more too

much). Anticipation (accumulates from generation to generation)  facial
muscle weakness  ptosis, drooping mouth.

o Fascioscapulohumeral Muscular Dystrophy: can’t puff cheeks, scapular

winging. Normal life expectancy.

o Limb Girdle Muscular Dystrophy 1: defective Caveolin-3

o Limb Girdle Muscular Dystrophy 2: defective assembly of A/B/G/D

sarcoglycan. Also can be defect in titin, calpain, etc.

o Congenital Muscular Dystrophy: mutation of laminin  muscle weakness,

MR, pectoral fold

 Muscular Dystrophy Treatments: physical therapy, pacemaker

 Treatment of DMD:
o Inject donor myoblast? Difficult because muscle cells don’t divide, so need to
inject a lot.
o Step Cell Therapy – either upregulate utrophin (homologous to dystrophin but in
fetus), or inject stem cells that would differentiate into myoblasts, or exon-
skipping

EXTRACELLULAR MATRIX DISORDERS

 Ehlers-Danlos Syndrome: defective fibrillar collagen synthesis weak connective

tissue stretchy skin, joint hypermobility

 Marfan’s Syndrome: remember fibrillin binds elastin. Fibrillin defect  weak elastic
tissue arachnodactyly (“spider fingers”), funnel chest, retinal detachment, aortic root
dilation.

 COPD (Emphysema): Absence of A1AT can cause emphysema because smoking

inhibits A1AT and smoking also recruits neutrophils to lungs releasing elastase. Elastin
loss à alveoli collapse  hyperventilation, barrel chest.

 Matrix Metalloproteinases
o MMP I = Collagenase I (so breaks down collagen I)

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o MMP II = Collagenase IV (so breaks down collagen IV, used by cell to invade
basal lamina, as well as chemotaxis)

 Glycoprotein vs. Proteoglycan

o Glycoproteins = adhesive (Gl for Glue)
o Proteoglycan/GAG = space filler, compression (Pr for Press)

 Hyaluronan is a type of “space filler – produced during wound healing, which need a lot
of cell-free space for repair cells to migrate. Its length is humongous – to create space
filler! It is not covalently linked to core protein so it is not compact.

 Gel of Vitreous Humor = collagen suspended in hyaluronan + lots of water à ultimate

shock absorber!

 Hyaluronan (a type of proteoglycan) vs. Other Proteoglycan

o Remember proteoglycan is usually a GAG + core protein
o Hyaluronan is a special exception! Is a GAG without core protein!

 Proteoglycan complexes can be Aggrecan (Cartilage) or Versican.

 Aggrecan proteoglycans attach to hyaluronan proteoglycan! (like paintbrushes on a
string)

 After growth factor binds to Perlecan or Syndecan (heparan sulfate), it has a better and
more convenient binding access to receptor on cell surface

 Diabetic Nephropathy: Perlecan and Syndecan (HSPG’s) downregulated  no

size/charge barrier in glomerulus  hyperglycemia  collagen glycosylated more
(sincethere’s more carbs floating around)  glomerular basement membrane thickens
with collagen.

 Cross-Links
o Collagen 6 cross-links Collagen 1
o Collagen 9 cross-links Collagen 2
o Fibrillin cross-links elastin

 Basal Lamina is a Specialized type of ECM:

o Integrin – Laminin – Perlecan/Entactin – Collagen IV

 ECM Composed of:

o Structural: collagen, elastin, fibrillin
o Glycoprotein Adhesives: laminin, fibronectin, entactin
o Proteoglycan Filler: proteoglycan (perlecan/syndecan), Hyaluron
 Two Organizations:
o Interstitial Matrix

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o Basal Lamina

 Basal Lamina vs. Other types of ECM!

o Basal Lamina: Integrin II - (Glycoprotein) Laminin – Perlecan (Proteoglycan) -
CollagenIV (Structure)
o Unspecialized ECM or stress fibers: Actin - Vinculin/Talin - Integrin I -
(Glycoprotein) Fibronectin – Syndecan (Proteoglycan) - CollagenI/III/V
(Structure)

 Fibronectin has these binding sites:

o For collagen
o For cell surface integrins (binding sequence is RGD)
o For heparin (Proteoglycan)
o For Fibrin

 Plasma membrane is weak, so need strong matrix on each side, hence ECM on the
outside of the cell membrane and actin matrix on the inside.

 Interaction between fibronectin and actin

o Integrin creates interaction between actin (inside cell) with fibronectin (outside
cell). So actin and fibronectin can align in same direction!
o So fibronectin is involved in cell spreading and migration (in the right direction),
as it creates a “paste” of cells that are properly aligned. Embryogenesis and
wound healing both need this direction and “paste” created by fibronectin.

 Fibronectin: 2 forms:
o Soluble = for blood coagulation
o Insoluble = for the “paste” that guide cell migration and growth (w/ alignment)

CELL-MATRIX INTERACTIONS DISORDERS

 Remember Vinculin is a focal adhesion (“foot hold”) protein, on the cytosolic side of the
cell – connect actin filament of stress fibers to ECM

 Integrins attach glycoproteins via its RGD sequence

 Integrin is the telephone between ECM and Cell, but they’re also the connection. So if
signals tell them to cluster, they will adhese the cell more and cause anchorage-dependent
growth. The reverse will cause cell motility.

 Remember glycoprotein IIb and IIIa in Glanzmann’s Thrombasthenia? They are platelet
integrins!!(β3)

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 Focal Adhesion vs. Hemidesmosome:

o Focal Adhesion: actin stress fibers - vinculin/talin – integrin – fibronectin –
collagen (I, III, V)
o Hemidesmosome: keratin – plectin (“plaque”) – integrin – laminin – collagen VII
– Collagen IV (of basal lamina)

 Bullous Pemphigoid: autoimmune attack on hemidesmosomes  epidermis detach from

dermis  blistering.

 Filapodia vs. Lamellipodia

o Notice filopodia are “filament feet”
o Lamellipodia are “lamellar feet”

 Old actin filaments are disassembled in back, and new ones are created in front à
crawling of cell. Contraction at back propels cell body forward.

 Chemotaxis:
o It’s interesting how the MMP and TIMPs are stored in ECM (Basal Lamina), as if
ECM has the keys to its own doors to allow cell to enter.
o Remember MMP is collagenase. MMPI digests Collagen I, MMPII digests
Collagen IV (basal lamina)

CELL-CELL INTERACTIONS DISORDERS

 Cell Junctions:
o Tight Jxns Occlude
o Adherens and Desmosomes anchor
o Gap junctions communicate

 TADG = from apex to base = tight jxn  adherens jxn  desmosomes  gap jxn

 Adherens vs. Desmosomes

o Adherens – connect via actin. A for “Actin”
o Desmosomes – connect via intermediate filaments

 Cadherins = “Calcium-Dependent Adherens”

 T vs A vs D vs G
o Tight Junction: Claudin/Occludin – ZO – actin
o Adherins: Cadherin - catenin/alpha actinin – actin
o Desmosomes: Cadherins (desmoglein/desmocollin) – Plakoglobin/Desmoplakin -
intermediate filaments
o Gap Junctions: 1000s channels = 2 connexons = 6 connexins

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 So both desmosome and hemidesmosome have “plaques” (Have parts of it named plec-
something or plak-something)

 You can tell which side of the cell is which by looking at where the zonula occludens is.

 Paracellular pathway = passage of free molecules between the cells. Zonula occludens is
the door to this pathway.

 Inflammatory Bowel Disease (i.e. Chron’s Disease or Ulcerative Colitis): occludin

(intight jxn) downregulated  paracellular pathway opened up  PMN (neutrophils)
get through

 Pemphigus: autoimmune attack on desmosomal cadherins (desmoglein/desmocollin)

 blistering  deadly infections

 Bullous Pemphigoid vs. Pemphigus

o Bullous Pemphigoid – autoimmune attack on hemidesmosomes
o Pemphigus – autoimmune attack on desmosomal cadherins

 Gap Junction:
o Eletrical: Peristalsis, Coordinated depolarization of heart muscles, uterine
contraction
o Chemical: cAMP passes between cells so can respond the same way to a hormone

 High Calcium level (from damaged cell) à closes gap junction, to prevent damage.

 Connexins
o Connexin 26 Mutation (in cochlea): deafness
o Connexin 50 Mutation (in lens): cataracts  blindness
o Connexin 32 Mutation (in peripheral myelin): Chargot-Marie-Tooth 
degeneration of peripheral nerves  atrophy of distant muscles, decreased deep
tendon reflex, “foot drop,” “high-stepping gait,” “high-arched foot,” “hammer
toes” (really mean nicknames for CMT!)

 Connexin 32 is unique in that it is actually an INTRAcellular gap junction, because it is

the communication between the different onion layers of schwann cells.

 Selectins:
o L-Selectin for leukocyte – for lymphocyte homing (addressins on lymphocytes
attach to the L-selectins on lymphoid organs, homing)
o P-Selectin for platelet
o E-Selectin for endothelial cell – leukocyte can “roll” on the E-selectin in the
bloodstream.

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 Lymphocyte Rolling, Trapping, and Extravasation

o Rolls on E-selectin – WEAK ADHESION SO IT CAN ROLL
o Then, eventually rolls onto ICAM , which binds to the lymphocyte’s integrin –
STRONG ADHESION, so it can stop and migrate through

 Leukocyte Adhesion Deficiency (LAD): β2 integrin mutation  impaired leukocyte

chemotaxis, extravasation, and therefore phagocytosis  life-threatening bacterial
infections.

COLLAGEN DISORDERS

 Collagen Structure:
o 3 residues/turn, L hand helix
o 3 stranded helix, R hand helix

 PXG repeats:
o Proline (P) – remember that it is bulky from Block 1?
o Hydroxyproline (X) – remember hydroxylated proline from Block 2?
o Glycine – connects all 3 strands with each other via H-bonding.

 MAKING A COLLAGEN:
1. Make 2 a1 & 1 a2 chains + signal peptide (preprocollagen)
2. Cleave signal peptide (procollagen)
3. Hydroxylate proline and lysine (via Vitamin C)
4. Glycosylate hydroxylysine
5. Disulfide bond aligns chain and initiates triple helix formation from CàN
6. H bonds form between hydroxyproline of procollagens.
7. Procollagen Peptidase removes Propeptides on both C and N end.

 Scurvy: Lack Vitamin C can’t hydroxylate proline  can’t H bond  can’t form
collagen  weak connective tissue  bleeding gums, nails, loose teeth, fatigue, etc.

 Remember:
o Collagen I = skin/bone/tendon
o Collagen II = Cartilage
o Collagen III = blood vessels, fetal skin
o Collagen IV (sheet-forming) = Basal Lamina
o Collagen VII = Anchoring

 Osteogenesis Imperfecta: Mutation in Collagen I (Glycine mutation at C-terminal) 

fragile bones, tooth abnormal, blue sclera.

 Ehlers-Danlos Syndrome: Mostly defect in Collagen I or V, but sometimes III, lysyl

hydroxylase (needed for procollagen bonding), or in converting procollagen to
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collagen.

 Alport Syndrome: defective Collagen IV  basal lamina defective basal lamina in

kidney doesn’t filter well  protein and blood in urine  kidney failure

 Goodpasture Syndrome: like Alport except autoimmune

 Epidermolysis Bullosa:
o Simplex: mutation in Keratin 5 and 14
o Junctional: mutation in laminin, integrins, hemidesmosomal proteins (@
junction)
o Dystrophic: mutation in Collagen VII (anchoring of hemidesmosomes to basal
lamina). “boy whose skin fell off”

 Achondroplasia: FGFR3 Mutation  FGFR3 (chondrocyte inhibitor) keeps getting

expressed!  chondrocyte proliferation is inhibited  no grow.
o Mnemonic: “Figs for Three.”
o FGFR = fibroblast growth factor receptor is a Receptor Tyrosine Kinase

 Other Collagenopathies:
o Achondrogenesis type II
o Kniest dysplasia – dwarf, enlarged joints
o Spondyloepimetaphyseal dysplasia
o Stickler syndrome - underdeveloped facial bones
o Campomelic Dysplasia – Mutation in SOX9  decrease Collagen II
o Thanatophoric Dysplasia – born dead. FGFR3 mutation, like achondroplasia
o Hypochondroplasia – also FGFR3 mutation, like achondroplasia

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