Proteopathic diseases and amelogensis imperfecta II Flashcards
what is amelogensis imperfecta
a group of developmental conditions that are genomic in origin which affects the structure and appearance of the enamel and nearly all of the enamel in every tooth
what is the prevalence of AI
1 in 700- 1 in 1400 depending on population
how can AI also be present
in cone rod dystrophy
in geneitcs how can AI be acquired
autosomal dominant
autosomal recessive
sex linked
and shows sporadic
phenotypes of AI
hyperplastic- pitting of enamel with an open bite
hypermineralised- rough soft enamel which is discoloured
hypermaturation- enamel normal thickness and very whiteish surface- can be mistaken as fluorosis
what is present in all cases of AI
in all cases teeth are sensitive, discoloured and prone to disintegration by post eruptive breakdown and idiopathic resorption
What are the key features of hyperplasia
pitting of enamel with open bite
what are the Key features of hyper-mineralisation
rough soft enamel which is discoloured
what are the Key features of hyper-maturation
normal thickness of enamel, whiteish enamel can be frequently mistaken for fluorosis
sensitive teeth
mutations in which genes are responsible for AI
amelogenin and enamelin
what is the wild type phenotype in mice
allele codes for phenotype most commonly
what has the Riken institute in Japan developed
a mass mutogenic library of mice
how have the Riken institute made this library
done this by feeding male mice ENUand this causes them to form point mutation and then interbreed with normal mice
what is ENU
ENU(N-ethyl-N-nitroso urea)- A HIGHLY POTENT MUTAGEN
how many dentitions do mice have
monophyodont dentition- only one permanent set of dentition
what is the mouse incisor characterised by on SEM
A herring-bow pattern with different levels of complexity
what allows the incisor to remain chiselled and sharp
the columnar and laminar structure of the HAP crystals which form rods with interods in between
what is the enamel characterised by
characterised by C axis hydroxyl ion where the Ca and Phosphate arrange
what is the enamel formation stages based on
tissue structure
histology of the adjacent enamel organ cells
enamel chemistry
what two stages are easily found
secretion stage
maturation stage
what are the characteristics of the secretion stage
characterised by:
secretion of matrix and the initial mineral phase and is complete when the full thickness of this complete tissue is deposited.
what are characteristics of the maturation stage
characterise by:
final matrix is removed and the final mineral content is acquired
complete when post eruption phase when it is not mediated by cells of the enamel organ
what stage is also included in the literature
transition phase( early maturation phase) between secretory and maturation
when does the transition phase occur
when the amelogenin is secreted
how are the phases concerned
as discrete
what are the characteristics of the early maturation phase
the ameloblasts are long and columnar and around 7 microns in length
the ER is also denser
what happens to the ameloblasts as the matrix is deposited in the maturation phase
the height of the ameloblasts decreases to around 3.5 microns in length
the ER is less dense
nucleus is also more in the centre of the cell
what is the mineral content in the secretion stage
around 30%
what is the mineral content in the early maturation stage
around 40%
what is the mineral content in the in the maturation stage
around 90%
what minerals increase in amount in the maturation stage
calcium and phosphate
what happens in the secretory stage
enamel proteins are secreted
what happens in the early maturation stage
enamel proteins stop being secreted
what happens in the maturation stage
proteins are removed and replaced by enamel
what is the enamel matrix mainly composed of
around 90% amelogenin
where is amelogenin found in chromosomes in humans
on the x chromosomes and Y
where is amelogenin found in chromosomes in rodents
on the x chromosome
if you have a heterozygous female rodent that reproduces what are the chances of getting AI
50% affected
50% unaffacted
if you have affected male rodent that reproduces what are the chances of getting AI
100% affected
what does the enamel look like in 100% affected offspring from XY affected males
no enamel is formed just a thin layer of descript material on top of the dentine
what does the enamel look like in 50% affected offspring from XX affected female
enamel is formed but it is just abnormal
what is lyonisation
where one copy of the x chromosome is turned off- gives rise to banded enamel in HETEROZYGOUS females with X LINKED AI
What does the histology of the enamel look like in heterozygous amelogenin mutant females
we can see strong eosinophilic vesicles in the enamel of the ameloblasts
more vascular in nature
herring-bow structure of the tomes process is lost
what are the eosinophilic vesicles packed with
amelogenin and ameloblastin- the proteins co localised within the vesicles
where does the failure lie if mutant amelogenin is accumulating in the ameloblasts
in the secretory pathway
what accumulates in the ameloblasts
mutant amelogenin due to an error in the secretory pathway
what does amelogenin mutation cause
loss of normal ER and golgi structure and the ameloblasts become engorged and filled with amelogenin filled vesicles
what causes ER stress
mutant amelogenin buildup which leads to activation o the unfolded protein response
what does the upr end up causing
attempts to restore proteostasis but will tip towards apoptosis with increasing time and stress
what chemical is used also as a chaperone
phenylbuterate which can act as a chaperone and help to refold chemical misfoldings
what drug can be used to treat urea cycle disorders
phenylbuterate
what is phenylbuterate used to treat
urea cycle disorders
how can phenylbuterate help mince
the visual shoring showed a marked improvement on the incisors but not on the molars
what is the mechanism of AI recovery by phenylbuterate
the phenylbuterate chaperones the proteins and mitigates the stress leading to ameloblasts not dying and the monolayer is retained allowing for healthy enamel to form
how long does it take for the UPR to switch from survival mode to death mode
around 6 days- thats when cells undergo apoptosis
what do mice with the enamelin mutation( S55I) show
massive defects in the enamel
less mineral density along the incisor
what is shown in the heterozygous S55I mutation in mice in regards to mineral content
good mineral content around the incisal edge but poor at the beginning
what is shown in the heterozygous S55I mutation in mice in regards to mineral content
poor all along
and poor enamel all along
is there a statically difference in the fold change of ENAM HETERO AND ENAM HOMO in BIP
no statisical difference
is there a statically difference in the fold change of ENAM HETERO AND ENAM HOMO in CHOP
statistical difference
what does the mutation in ENAM S55I show
that it inhibits the ameloblasts secondary pathway and leading to ER stress and the UPR which leads to slight recovery and the deposition of normal enamel but the enamel secreted after was abnormal
what can fluoride trigger
an unfolded protein response which could trigger ameloblast function and or survival and lead to fluorotic enamel defects causing fluorosis
it doesnt cause protein misfolding just activates in some way
