Cell biology theme 3 Flashcards
What is the most basic function of the cell cycle ?
duplicate DNA
separate into genetically identical cells
Besides DNA what else duplicates ?
macromolecules
organelles
doubles in size
what are the 4 phases of the cell cycle
M phase (mitosis and cytokinesis)
G1 phase
S phase these make up interphase
G2 phase
What happens in the S phase ?
DNA replication
What happens in G1 and G2 ?
the cell continues to grow and monitors the external and internal environment
Why do cells need to monitor the external/internal environment ?
ensures the conditions are suitable for reproduction and preparations are complete before the cell commits to S phase and M phase
What are the 2 mechanical process that take place in the M phase ?
separation of the duplicated chromosomes
division of the cytoplasm
Which assemblies carry out the nuclear and cytoplasmic divisions ?
nuclear division is carried out by the mitotic spindle
cytoplasmic division is carried out by the contractile ring
What is the mitotic spindle made of ?
microtubules and motor proteins
it arises from centrosomes
What is the contractile ring made of ?
Actin and myosin microfilaments
arranged in a ring at the equator
What happens during prophase ?
chromosomes condense and the mitotic spindle assembles
What happens in prometaphase ?
nuclear envelope breaks down and spindle attaches to chromosomes
What happens in metaphase ?
chromosomes align at the equator of the spindle
What happens in anaphase ?
paired chromatids separate to form daughter chromosomes , migration to opposite poles
What happens in telophase ?
the nuclear envelope re-assembles and the contractile ring assembles
What happens in cytokinesis ?
the completed nuclear envelope now surrounds the chromosomes
the contractile ring pinches to create 2 daughter cells and cells enter G1.
What are kinetochores ?
microtubules from the spindle grab hold of chromosomes at the kinetochore , kinetochores are protein complexes that form at the centromere of each chromosome.
How do kinetochores recognise the centromeres ?
there is a special DNA sequence at the centromeres , if this is altered the kinetochores fail to assemble and chromosomes dont segregate
What are the 3 phases of interphase ?
G1
S
G2
What happens during interphase ?
allows cell to duplicate contents
monitor the external and internal environment befre committing to S phase
Why do eukaryotic cells need a cell cycle control system ?
this guarantees the events of the cell cycle occur in the correct sequence
How is progression through stages of the cell cycle monitored ?
regulation at cell cycle checkpoints
receive feedback on processes
What are the cell cycle checkpoints ?
G1 to S
G2 to M
M to G
What is checked at the progression from G1 to S ?
the environment is favourable for DNA replication
What do cells require to avoid delayed progress through G1 ?
nutrients are signals from the extracellular environment
What is checked at the progression from G2 to M phase ?
the DNA is undamaged and fully replicated
What is ensured during mitosis ?
chromosomes are fully attached to the spindle
What do cells need to receive to grow ?
signals (esp during G1)
What is the G0 phase ?
a phase where cells arent dividing/preparing to divide because there is a lack of nutrients and growth factors
Which cells are stuck in G0 ?
Neurones and red blood cells - they have reached their mature state and dont need to divide again
What are mitogens ?
signals that stimulate cell division - cells only divide when they receive mitogens
What are growth factors ?
stimulate cell growth when the cells are not dividing
What are survival factors ?
they inhibit apoptosis and therefore promote cell survival
disruption in cell signaling pathways can lead to what ?
cancer
How is the cell cycle controlled ?
activating and deactivating proteins that initiate DNA replication , mitosis and cytokinesis
What controls the activity of these cell cycle initiator proteins
kinases - the activity of kinases follows a cyclic pattern as they are only activated when approproate
what do kinases depend on ?
cyclin
What does cyclin do ?
forms a complex with kinases - cyclic changes in the amount of cyclin drive the assembly and activation of these complexes - they trigger various cell cycle events
different CDK complexes …
trigger different cell cycle events ?
How are mitogens and CDKs linked ?
mitogens promote cell division by stimulating the accumulation of cyclin
how are CDKs switched off ?
by destroying cyclin - this happens via an anaphase promoting complex which tags the cyclin with ubiquitin - the CDK is inactivated.
What is apoptosis ?
the elimination of unwanted cells by programmed cell death - it is a regulated and normal event
How is the number of cells in a community controlled ?
by controlling the rate of cell division
What is necrosis ?
accidental cell death - die to disease , injury or failiure to supply adequate blood
How does necrosis occur ?
cells swell and undergo lysis
the contents is released into tissues
this triggers the inflammatory response which leads to damage.
it is unprogrammed and unregulated
How does apoptosis occur ?
the activation of an inbuilt suicide pathway
cells develop irregular blebs - the cell shrinks and condenses
the cytoskeleton collapses
the nuclear envelope disassembles
why is apoptosis described as clean death ?
the alteration in the cell surface atracts phagocytic cells
they engulf the apoptotic cell before it spills its contents
Which molecules are responsible for apoptosis ?
a family of proteases - called caspases
`What are the inactive form of caspases called and why are they activated ?
procaspases
they are activated in response to signals that induce apoptosis
How can apoptosis be triggerred by caspases ?
apoptosis is triggered by a protease cascade where initiator caspases cleave and activate downstream caspases - this amplifies and broadcasts the response.
Is the caspase cascade reversible or not ?
no- it is irreversible the decision to die is highly regulated
How can you activate a caspase ?
remove a peptide from the procaspase
What is the function of activated caspases ?
cleave other caspases in a cascade - activate them
cleave nuclear lamins - structural proteins in the nucleus - nuclear fragmentation
Activate DNase which turns DNA into fragments
cleave the cytoskeleton loosing contact with the ECM
in an apoptotic cell how will the DNA fragments appear ?
as a ladder as the DNA is now in fragments
Why is apoptosis needed in development ?
to remove tissue and to model organs into the correct shape. to allow the formation of complex tissues
Why else is apoptosis needed ?
to control cell numbers (eg. removal of autoreactive T cells)
removal of infected cells (eg. cytotoxic T cells can kill virally infected cells)
Removal of stressed or damaged cells (DNA)
What signal types can induce apoptosis ?
hormonal signals
cytokines
direct signals from a contracting cell
How does the death receptor Fas work ?
a cytokine signal from the TNF family causes a death receptor be expressed
this is activated by binding of a ligand
triggers the death inducing complex- caspase cascade
Which signals suppress apoptosis ?
survival factors
mitogens
growth factors
How can survival factors control the number of nerve cells ?
survival factors are secreted by target cells
they are picked up by nerve cells
survival factors suppress the suicide program
there is an over production of nerve cells so some cells wont receive the survival factor - apoptosis of these cells occurs
this ensures that the number of nerve cells matches the number of target cells
How do mitogens suppress apoptosis ?
they bind to receptors that trigger intracellular pathways that release molecular brakes blocking transition from G1 to S.
how do growth factors suppress apoptosis ?
they activate intracellular pathways that lead to an accumulation of certain proteins required for the cell to grow.
What are integrins and how do they promote cell survival?
fibronectin , a glycoprotein attaches to collagen (at the membrane of fibroblasts) via integrin which is attached to actin in the cell cortex
this inhibits apoptosis as there is a contact with the ECM
which molecules regulate activation of caspases ?
members of the Bcl2 family - some promote caspase activation others inactivate caspases leading to apoptosis being inhibited
What determines whether a cell dies or survives ?
the balance of activities of different members of the Bcl2 family
How can mitochondrial injury lead to apoptosis ?
damaged mitochondria leak cytochrome C (from between the inner and outer membrane) into the cytosol
Cytochrome C activates caspases - this is the action of BAX and BAD proteins (members of Bcl2)
this leads to a caspase cascade
some Bcl2 members can also inhibit apoptosis
damaged DNA leads to what being activated ?
p53- a protein
what does activation of p53 do ?
it inhibits CDKs
Excessive damage to DNA causes what ?
a large amount of p53 being activated
this overcomes a threshold
overcoming the threshold means apoptosis is activated as Bcl2 members are activated.
What are diploid cells ?
they have 2 versions of each chromosome
one from each parent
only the sex chromosomes differ
Where does meiosis only occur ?
in the ovaries and the testes
What is the process of meiosis ?
DNA replication
duplicated chromosomes attach to the corresponding homolog
2 sets of cell division
diploid cells turn into haploid gametes
the assignment of each homolog to a haploid cell is …
random - each gamete receives a mixture of maternal and paternal chromosomes creating diversity
what do the 2 separate cell divisions entail ?
the first division separates the chromosomes at anaphase
the second division separates the sister chromatids at anaphase
What is recombination ?
the exchange of fragments of maternal and paternal homologous chromatids
when does recombination occur ?
during prophase of meiosis 1
How does recombination lead to genetic variation ?
produces individuals with novel assortments of alleles
can provide an evolutionary advantage
Are chromosomal abnormalities acquired or inherited ?
they are acquired
What are most chromosomal abnormalities to do with?
structure and number - they produce abnormal embryos that are not viable
What is aneuploidy ?
the loss or gain of one or more chromosomes
What is an example of aneuploidy ?
trisomy 21 - where an individual has an additional chromosome 21 - 3 in total leading to Downs Syndrome
What is polyploidy ?
the addition of one or more complete haploid complements (46,69,92 etc)
What is an example of polyploidy ?
triploidy- where individuals have 3 sets of chromosomes (69) leads to spontaneous miscarriages.
What is chromosome non-disjunction ?
the failure of homologous chromosomes/sister chromatids to separate properly during cell division. leads to gametes with an unusual number of chromosomes
Why does non-disjunction usually occur ?
inappropriate spindle formation
What is translocation ?
a chromosomal abnormality caused by rearrangements of parts between non homologous chromosomes- they are usually identified by karyotype analysis.
What is the 9:22 translocation ?
exchange of genetic material between chromosomes 9 and 22 - this results in the formation of the philadelphia chromosome - a chromosome 22 derivative
What are structural abnormalities in chromosomes ?
includes chromosome breakage and reunion in a new configuration.
What are the p and q regions of the chromosome ?
refers to the parts of the chromosome separated by the centromere - the p is the short region and q is the long region.
what is the 15q12 chromosome partial deletion ?
the long (q) arm is deleted on one copy of the chromosome. it increases the risk of birth defects and developmental delay.
what is a karyotype ?
the full complement of chromosomes in the cells of an individual
how do we create a karyotype ?
the metaphase spread
all cells are given phtochemagglutinin which inhibits the formation of the spindle
cells are stuck in metaphase and are condensed
What do we use karyotypes for ?
observing number and shape
cytogenetics
What is chromosome painting ?
stain chromosomes based on DNA sequences usin complementary probes
chromosomes have different banding patterns and size
What is NIPD ?
non-invasive prenatal diagnosis
Analyses the DNA fragments present in maternal plasma for sex determination etc.
What are the 2 types of DNA sequences ?
Extragenic
Genes
Genes can be classified as what ?
Unique
Gene families
Gene superfamilies
What are unique genes ?
Pseudogenes which appear as genes and are not expressed
How can extravehicular sequences be classified ?
Low copy
Moderately repetitive
Highly repetitive
What are tandem repeats ?
Satellite
Mini satellite
Micro satellite
What is satellite DNA ?
Large arrays of repaying non coding DNA
Genes code for what
Mainly proteins
Non coding RNA
Prions (misfolded proteins)
What are alleles ?
Alternative forms of a gene found at the same locus on homologous chromosomes
Mutations can be on what levels ?
Nucleotide levels
Or the chromosome level (structure and number)
What are germline mutations ?
Occur in germ cells
Responsible for inherited diseases
What are somatic mutations ?
Occur in adult life or development
Affect a limited number of cells
They can accumulate in cells with age leading to cancer
What is a loss of function mutation ?
Reduced activity
Loss of gene product
Occurs with null alleles and gene deletion
What is a hypomorphic mutation ?
The altered gene product expresses as lower level of activity
What is haploinsufficiency ?
A LOF mutation occurs in a heterozygous individual - the remaining functional copy was nit adequate to produce the function needed
What is a gain of function mutation ?
The gene product acquires a new function and increased activity
What is dominant negative mutation ?
A LOF function mutation occurs die to the interference of the mutant gene product with normal gene product of corresponding allele
What usually causes chromosomal abnormalities ?
Chromosome non disjunction
What is aneuploidy ?
Loss or gain of one or more chromosomes
What is polyploidy ?
The gain of one or more complete sets of chromosomes (46,69)
What are de novo mutations
They are nit inherited
Bc they result in embryonic lethality
What causes structural chromosomal abnormalities ?
Chromosome breakage and abnormal reunion
What is translocation ?
Transfer between non honologous chromosomes
Robertsonian and reciprocal
What is a reciprocal translocation ?
2 fragments from 2 different chromosomes and swap places
What is a robertsonian translocation ?
Occurs in acrocentric chromosomes where chromosomes break ball near the top and long arms fuse to form a chromosome
What is inversion ?
Chromosome segments are reversed in position
Pericentric- involving the centromere
Paracentric- involving one chromosome arm
What is a nucleotide transition substitution ?
When a purine is exchanged for a purine , or a pyrimidine for a pyrimidine. (purines are C and T) (pyramidines are A and G)
What is a silent substitution ?
encodes for the same amino acid and has no effect on the protein
What is a missense substitution ?
encodes for a different amino acid so the protein structure is altered.
What is a nonsense mutation ?
introduce a stop codon which results in loss of gene expression
What is a splice site mutation ?
results in exon skipping or intron retention
What does it mean by a missense mutation being conservative or non-conservative ?
depends on the new properties of the new amino acid eg if it changes from acid to basic
What can multiples of three deletions lead to ?
in frame deletions
can delete amino acids
affects protein structure and stability
What can non multiples of three deletions lead to ?
frame shifts
premature termination
loss of gene expression
What causes structural changes in chromosomes ?
chromosome breakage and abnormal reunion
unequal crossovers in homologous combination
What are ring chromosomes ?
a broken chromosome segment forms a ring
What is an isochromosome ?
when the arm of the chromosome is lost and the other arm is duplicated
What is a balanced change ?
no loss of DNA
usually harmless
`what is an unbalanced change in DNA ?
loss of DNA
can lead to severe disease and syndromes
What is a trinucleotide repeat expansion ?
where the repeat sequence becomes unstable as the gene ex
What is the effect of a trinucleotide repeat expansion on the huntington gene ?
it leads to qualitative changes in the gene product which leads to aggregation of the product in the CNS.
What can larger gene insertions lead to ?
partial gene duplications ?
How can mutations be caused by errors in DNA replication ?
proofreading mistakes of DNA polymerase
proofreading usually prevents mispairing of bases however there can be mistakes
How can chemicals lead to DNA mutations ?
chemicals
products of metabolism
lead to the formation of DNA adducts
What is depurination ?
A chemical reaction where ethe base is released - a deletion
What is deamination ?
the removal of an amine group from cytosine - it froms uracil- hence a substitution
How can physucal damage be caused to DNA ?
ionising radiation causes the double hellux to break
What does UV light do ?
leads to the formation of thymine dimers which leads to errors in DNA replication and eventually nucletodie deleetion
What does mismatch repair do ?
it corrects mismatched bases introduced in DNA replication- cells defective in this have high mutation rates
What is nucleotide excision repair ?
removing the thymine dimers and DNA adducts
What is base excision repair ?
removes single abnormal bases
What is post replication repair ?
corrects double stranded breaks in homologous combination with a sister DNA molecule - ensures no loss of DNA
What is a multigene family ?
genes that have similar functions that have arisen through gene duplication - they can be physically close or dispersed in clusters
What are classic gene families ?
genes that show a high degree of sequence similarity
eg.hox genes
What are gene superfamilies ?
genes that have limited sequence similarity but are functionally related
have similar structural domains
What are pseudogenes ?
they closely resemble genes
not functionally expressed
How can an accumulation of somatic mutations lead to cancer ?
if a tumoure suppressor gene is lost leads to excess cell prolifferation activates an oncogene more TSG are lost metastasis
What are the consequences of beta globin mutations in cell anaemia ?
A-T transversion leads to an amino acid substitution
reduced solubility
intracellular precipitates
sickle celled erythrocytes
What are point mutations ?
changes that effect a single nucleotide pair
How can you determine the relative genetic and environmental influence on variation/disease ?
studying identical and fraternal twins
What is a mutation ?
The DNA variant has a frequency of less than 1% in the population
What is a polymorphism ?
occurs when the DNA variant has a frequency of more than 1% in the population and has at least 2 alleles
What is an SNP ?
a single nucleotide polymorphism
arise from replication errors by DNA polymerase
evenly distributed in genes and extrgenic sequences
what is a haplotype block ?
a group of specific alleles that are likely to be inherited together - due to homologous recombination
How are highly repetitive DNA sequences formed ?
derived from mobile DNA elements
transposons and retrotransposons
What do transposons do ?
they move DNA pieces from one place to another using a cut and paste mechanism , movement is mediated by an enzyme
What do retrotransposons do ?
they work via an RNA intermediate
Reverse transcriptase makes cDNA
this is free to integrate in the genome
the cDNA can be a hybrid of viral and human DNA
What does retrotransposition mediate the generation of ?
generation of model exons
regulatory regions
exon shuffling
what is the genotype of an organism ?
the genetic constitution of an individual
How many autosomes do humans possess ?
44
A gene with 2 alleles has how many possible genotypes ?
3
What is the phenotype ?
the observed characteristics of an individual
What determines the phenotype ?
genotype
environmental factors
What does penetrance mean ?
the proportion of individuals who carry a specific genotype and the associated phenotype
can be complete (100%) or incomplete
What is expressivity ?
quantitative or qualitative variations in the phenotype amongst individuals carrying a specific genotype
eg. mild , moderate and severe
What are monogenic disorders ?
they effect one gene
they are rare
What is a dominant inheritance pattern ?
the effect of one allele masks the contribution of the other allele
What is a recessive inheritance pattern ?
for the phenotype to be expressed the individual mist hold 2 mutant alleles
What is an autosomal inheritance pattern ?
the diseased gene is present on an autosome
What is X-chromosome linked ?
the disease allele is present on the X chromosome
What is co-dominant ?
alleles that are equally dominant and contribute to the phenotype equally
What is X-linked dominant ?
the dominant gene is carried on the X chromosome
What is pseudoautosomal ?
regions that are homologous on X and Y chromosomes and are inherited as if they were autosomal
What are features of autosomal dominant inheritance ?
both sexes are equally affected transmission of the disease from male to male occurs in every generation homozygotes usually die in utero 50% diseases risk
What are the features of autosomal recessive inheritance ?
both sexes are equally affected
does not occur in every generation
affected children likely to have carrier parents
25% disease risk , 50% carriers
What are the features of X-linked recessive ?
the diseases only effects males (males only have 1 X)
females are carriers
affected males have unaffected parents , not every male is effected
no male to male transmission
25% disease risk
Why do complex diseases not follow mendelian inheritance patterns ?
complex ateiology
many symptoms
high varaiation
What are additive effects of loci in polygenic traits ?
there is an equal contribution of the involved loci
What are non-additive effects of loci in polygenic traits ?
there is an unequal contribution of the involved loci
What does it mean if a disease is multifactorial ?
the diseases are influenced by the interaction of both genetic and environmental factors
several genes with additive effects form a what ?
a normal distrubution
What can be used to determine the risk of getting a disease in the general population and family relatives ?
a liability threshold model
the threshold for developing a disease combines all the environmental and genetic factors
the normal distribution shifts to the right for family members
what are the 3 stages of human development in the embryo ?
cleavage
embryonic period
foetal period
What happens during cleavage ?
cell proliferation
cells respond to teratogens (birth defect inducing systems)
What happens in the embryonic period ?
morphogenesis
4-10 weeks craniofacial development
What happens during the foetal period
embryo develops into a foetus
cell differentiation
What causes organ disorders ?
impairment of early embryonic processes such as cell differentiation and morphogenesis
How does impairment occur ?
genetic factors - mutations in developmental genes or chromosomal abnormalities
environmental factors
or a combination
What does it mean by if a craniofacial disorder is syndromic ?
the defects occur in combimnation woith other anomalies
this is because the mutant gene has multiple functions during the development of different organisms
eg. EDA1 mutations in hypohidrotic ectodermal dysplasia
What does it mean by if a craniofacial disorder is non-syndromic ?
the defects aren’t associated with other anomalies
this is because the defective gene function might not be compensated by other genes
What are early defects (craniofacial disorders) ?
they affect developmental processes of tissues
eg. cleft lip/palate is caused by abnormalities in genes that control facial development
What are late defects ?
they affect cell differentiation and are often to do with cell types that form specialised tissue
eg. amelogenesis imperfecta is caused by abnormalities with the ameloblasts that produce ename;l
What are the 3 different cell sheets that a zygote produces as it divides ?
mesoderm
ectoderm
endoderm
these are germline derivatives that fold into an organism and each sheet develops into structural components
What do genetic regulators do to cells ?
they instruct cells to express certain genes which determine the type of cell
What determines the type of genetic regulators a cells produces ?
cell signalling
Gene mutations in regulatory proteins in early stages of differentiation lead to ?
major abnormalities
Gene mutations in regulatory proteins in later stages of differentiation lead to ?
minor abnormalities
What regulates the expression of cell signaling molecules ?
combinations of transcription factors
what do signaling molecules do after being secreted ?
they bind to corresponding receptors
What happens after the signaling molecule binds to its corresponding receptor ?
the signals are induced and then transduced and integrated from many separate pathways leading to the activation of other transcription factors
eventually cell differentiation occurs
How many pharyngeal arches does the embryo have ?
3- first,second and third
What does the embryo consist of ?
3 pharyngeal arches
a heart
and somites
What are somites ?
compartments that the body is subdivided into that is responsible for the development of certain structures
What does each pharyngeal arch do ?
forms specific nerves , arteries , muscles and skeletal elements
which pharyngeal arch undergoes processes to form the mandible and the maxilla ?
the 1st arch
What do CNCs do ?
they migrate along specific pathways from the early brain forward into the arches
they form the majority of craniofacial features (face jaws and teeth)
the cell is programmed to its destination in the embryo
how are CNCs regulated ?
a code of HOX genes
CNCs express a variety of HOX genes which determine the shape and structure of vertical bodies
mutations in which genes lead to craniofacial disorders ?
the head is not controlled by HOX genes but HOMEOBOX genes
mutations in HOMEOBOX genes lead to craniofacial disorders
What are the stages of facial and palatal development ?
formation
growth that is forward
fusion of the correct tissues and the correct time and fucntion
What is a cleft lip and palate ?
different types with variable expressivity/severity
can be syndromic (treacher collins) or non syndromic
missing teeth associated (share a similar gene)
non syndromic through to have genetic disposition and tiggered environmentally
What are the characteristics of treacher collins syndrome ?
hypoplasia of the mandible and facial cheek bones
incomplete penetrance
AD inheritance
heterozygous mutation for genes in ribosome biogenesis means CNCs die by apoptosis before migrating into the craniofacial region.
not sever - happlosufficient
What is the hedgehog signaling molecule ?
important in controlling the facial midline
small amounts - cyclopia
abnornally high- facial duplications
What is craniosynostosis n?
premature fusion of the cranial sutures
skull is too small for the brain to grow
pressure - mental abnormalities
sagittal or coronal
How does the FGFR2 mutation lead to craniosynostosis ?
a receptor is cpded for
mutation means the receptor is constantly active
syndromic- other genetic influences - limb abnormalities
how do tooth related disorders arise ?
mutations in genes that code for genetic regulators that control tooth development
What are the stages of tooth development ?
initiation
morphogenesis
differentiation
Defects during initiation affect ?
tooth number and identity
defects during morphogenesis affect ?
tooth shape
defects during differentiation affect ?
structure of hard tissues
enamel and dentine
what is hypodontia ?
less than 6 missing teeth (excluding the third molars)
What is oligodontia ?
6 or more missing permanent teeth (excluding the third molars )
What is anodontia ?
very rare - no teeth
missing teeth is syndromic or non syndromic ?
both
What is hyperdontia and how does it arise ?
super-numerary teeth
duplication of the dental lamina by an over dosage of genes leads to a second row of teeth forming
What causes downs syndrome ?
trisomy 21
What dental abnormalities are associated with Downs syndrome ?
hypodontia delayed eruption dental tissue hypoplasia periodntal tissue malocclusion
What is amelogenesis imperfecta ?
AD/X-linked
mutations in the enzyme that regulate the ECM
hypoplasia - reduced enamel matrix formation
hypomineralisation - normal enamel but reduced mineral content
hypomaturation- normal enamel thickness but mottled and softer teeth
What is dentinogenesis imperfecta ?
defects in dentine formation (odontoblasts)
blue/grey or brown teeth
bulbous crowns and short rootd
enamel more likely to be chipped as denetine is shock absorber
mutations in DSPP ggenes
What is osteoporosis ?
short and fracture prone individuals
delayed tooth eruption and increased dental caries
failure to resorb bone leads to caries
What is Ehelra-Danlos Syndrome ?
connective tissue effected
elastic and fragile skin periodontitis
fragile oral mucosa - internal bleeding
small fragile teeth
