Connective Tissue Disorders Flashcards
What are complex tissues organised by?
the ECM
what’s bigger, the ECM or the cells it organises?
the ECM
what are basement membranes?
specialised ECM to organise epithelial cells
how are different parts of ECM derived?
distinct arrangements of collagen
which type of collagen is specific to basement proteins?
collagen IV
what structure does collagen IV assemble into?
a 2D net
why does collagen IV assemble into a net not fibres? (4)
- non collagenous regions aren’t cleaved- so can’t pack parallel
- crosslinking of 4 triple helices to form a colied coil
- interuption in Gly-X-Y repeats cause flexibility
- there’s end-end interactions between the non collagenous ends
describe the creation of collagen IV?
made in ER
each chain made then co-transitionally transported through the ER
asseembles into 3 molecule triple helix - driven by C-terminal non-collagenous domain
- the trimers interact to form a hexamer (2x3)
at the 7S domains there’s a central interaction to form a tetramer of trimers
- lattice builds of these to form BM
how many collagen IV gnes?
6
what are the 3 possible trimers of collagen 4 possible?
a1 a1 a2
a3 a4 a5
a5 a5 a6
what is glomerular BM?
filter of glomerules in kidneys
a particularly thick BM
fluid pushes through to give urine
what trimers are used in kidney BM?
in development it’s a1 a1 a2
as it matures it switches to
a3 a4 a5
what collagen trimers are used in most tissue?
a1 a1 a2
what is alports syndrome?
- loss of a3 a4 a5
patients are fine/healthy in childhood as modt tissues are a1 a1 a2
a3 a4 a5 has more cross links, making it more restiant to pressure- so in alports syndrome, adult kidneys have glomerular Bm degradation
what causes early onset alports?
large gene rearrangements
non-sense mutations
what causes late onset alports?
missense mutations, disrupt gly-x-y repeats
condensed cysteine reduces crosslinking
what is laminin?
a major component of BMs that self-assembles into a network to present binding sites for cells
what’s laminin made up of?
3 chains
what are the 3 chains that make up laminin?
a, B, y
what shape does the laminin take?
cruciform
describe the structure of laminin?
3 chains form a coiled coil shape
brought about by repeated sequence of 7 Amino Acids
disulphide links beween each end of coiled- coil domains
what’s similar between collagen IV and laminin networks?
they form spontaneously in vitro
how is the laminin and collagen network linked?
by accessory molecules
are there more laminin or collagen isoforms?
laminin
how many of each laminin chain are there?
5a, 3B, 3y
are all laminins essnetial through the body?
no- only some- these are ubiquitous
what does the diversity of laminin isoforms results in (pathologically)?
a range of tissue specific genetic diseases
what’s pierson syndrome?
rare lethal condition
lack of laminin II (which is usually found in glomerular BM, eye and synaptic BM) causes renal disease, eye abnormalities and muscular issues
what do specific laminin isoforms in the epidermis link?
to the underlying collagen in the dermis
what is Epidermis Bullosa?
a related group of conditions where skin blisters following mechanical trauma
mutations affect mechanical strength or dermal-epidermal junction
what isoform is laminin 5?
a3:B3:y2
what does laminin 5 do in BM?
links cell surface adhesion proteins (integrins) in structures called hemisomes to underlying collagen
what does mutation of laminin 5 cause?
junctional epidermis bullosa
what is junctional epidermis bullosa?
- lethal within first few months after birth
- recessive mutation
- mice model-normal phenotype at birth, develop blisters and die by day 3
what can cause defect in laminin 5?
mutation in laminin B3
what does gene therapy for laminin B3 chain mutation do?
- uses retrovirus to deliver functional Laminin B3 gene to patients
- causes skin healing
what do cell surface receptors for laminin link?
epithelial cells to the basement membrane
what are integrins?
cell- ECM adhesion receptors found in most cells
what does deletion of B4 integrin lead to?
same phenotype as Laminin 5- not living long past birth
what’s Epidermis bullosa simplex?
- milder than other forms
- blisters from mechanical stress
- heals w/o significant scarring
- less lethal than junctional EB
- associated with mutations in keratin 4+5
what tissues are BMs found in? (5)
- kidney glomerulas
- epithelium
- muscle
- blood vessel
- neuromuscular junction
muscles transmit force via
a secure attachment to BM
what laminin isoform is in muscle-tendon BM?
laminin 2 (a2:B1:y1)
what laminin isoforms are in neuromuscular junctions?
laminin 2 (a2:B1:y1) and (a5:B2:y1)
overall what are muscular dystrophies?
defects in muscle attachment to BM
how many main ways does the BM attach to muscle?
2
what are the 2 ways the BM attaches to muscle?
1) Laminin (BM)–> Integrin (cell)
2) Laminin (BM) –> Dystroglycan (cell)
which parts of the BM- cytoskeleton linkage can have disruptions to cause MD? (5)
- Lamin
- integrin
- dystroglycan
- collagen
- dystrophin
what type of dysfunction leads to congenital MD?
laminin
what type of dysfuncction leads to Duchenne/ Becker MD?
dystrophin
which type of dysfunction leads to bethlem MD?
collagen
compare the phenotype of duchenne and becker MD
Duchenne- onset childhood, wheelchair by 10 years, death 30s
Becker- childhood onset, wheelchair by 40s, normal death age
is there a cure for MD?
no
what causes 50% of congenital MDs?
Laminin a2 chain mutation
when do congenital MDs manifest?
after birth/ first few years
what are the symptoms of congenital MD? (4)
muscle weakness
delayed motor development
joint problems
PNS and CNS defects
is the phenotype of congenital MD worse or better if there’s a complete loss of laminin a2 as opposed to partial loss?
worse
what type of gene inheritance is congenital MD?
autosomal recessive
what does loss of Integrin a7 cause?
progressive MD
what does loss of integrin B1 cause?
no MD
does the dystrophin complex function with or independently of the laminin- integrin complex?
independent
what’s the most common type of MD?
Duchenne
what type of gene inheritence in duchenne MD?
X-linked
what component is affected in duchenne?
dystrophin
if there’s issues with both dystrophin and integrin would the phenotype be worse than one on its own?
yes
what’s the difference between duchenne and becker MD?
Duchenne is caused by a complete loss of dystrophin
Becker is caused by a partial loss of dystrophin
how big is the dystrophin gene?
very large- largest in genome
is it possible to deliver a dystrophin gene by a retrovirus like laminin B3?
no- too big
how can duchenne symptoms be reduced to becker like?
further cutting of gene
are there any known mutations of dystroglycan?
no- probably not viable (however MDs are associated with it)
what is Fukuyama Congenital MD?
- predominant in Japan
- severe muscle degeneration
- brain abnormalities
what causes Fukuyama congenital MD?
insertion into Fukutin gene
Fukutin associated with glycosylation of dystroglycan
can’t bind to laminin w/o
what causes the degenerative aspect of MD?
defective control of apoptosis- overactivation of apoptotic factors
how can apoptosis be reduced in MD?
loss of Bax/ BCL-2
