Huntington Disease

Type of inheritance?

Gene affected?

Hallmark (characteristic) of disease?

Autosomal Dominant

HD (huntington) Gene

Mental Retardation, choreic movements

Achondroplasia

Type of inheritance?

Gene affected?

Hallmark (characteristic) of disease?

Autosomal dominant

FGFR-3

Dwarfism

NF Type 1

Type of inheritance?

Gene affected?

Hallmark (characteristic) of disease?

Autosomal dominant

NF1

Cafe-au-lait spots, nurofibromas

Marfan Syndrome

Type of inheritance?

Gene affected?

Hallmark (characteristic) of disease?

Autosomal Dominant

FBN1(fibrillin)

tall stature, long/slender fingers

Familial Hypercholesterolemia

Type of inheritance?

Gene affected?

Hallmark (characteristic) of disease?

Autosomal dominant

LDL Receptor

Elevated serum cholesterol (death by MI by age 20)

Hurler Syndrome

Type of inheritance?

Gene affected?

Hallmark (characteristic) of disease?

Autosomal Recessive

a-L-iduronidase

Lysosomal storage disorder

Hereditary Hemochromatosis

Type of inheritance?

Gene affected?

Hallmark (characteristic) of disease?

Autosomal Recessive

HFE

Iron Overload (increases absorption too much)

Cystic Fibrosis

Type of inheritance?

Gene affected?

Hallmark (characteristic) of disease?

Autosomal recessive

CFTR

>1000 mutations reported

Sickle-Cell anemia

Type of inheritance?

Gene affected?

Hallmark (characteristic) of disease?

Autosomal Recessive

B-globin

Phenylketonuria (PKU)

Type of inheritance?

Gene affected?

Hallmark (characteristic) of disease?

Autosomal recessive

Phenyalanine Hydroxylase (PAH)

leads to a build up of substrate, need to change diet within a month of birth

B-thalassemia

Type of inheritance?

Gene affected?

Hallmark (characteristic) of disease?

Autosomal recessive

B-globin

hemoglobinopathy

Tay-sachs

Type of inheritance?

Gene affected?

Hallmark (characteristic) of disease?

Autosomal Recessive

HexA

Lysosomal storage disorder

Fragile X Syndrome

Type of inheritance?

Gene affected?

Hallmark (characteristic) of disease?

X-Linked Dominant (only one)

FMR1

Mental retardation

Hemophilia A

Type of inheritance?

Gene affected?

Hallmark (characteristic) of disease?

X-linked recessive

Factor VIII

Hemophilia B

Type of inheritance?

Gene affected?

Hallmark (characteristic) of disease?

X-linked recessive

Factor IX

Lesch-Nyhan Syndrome

Type of inheritance?

Gene affected?

Hallmark (characteristic) of disease?

X-linked recessive

HGPRT

Self-mutilation

Duchenne Muscular Dystrophy

Type of inheritance?

Gene affected?

Hallmark (characteristic) of disease?

X-linked recessive

Dystrophin

Weakness and loss of muscles (Severe)

Becker musclular dystrophy

Type of inheritance?

Gene affected?

Hallmark (characteristic) of disease?

X-linked recessive

dystrophin

weakness and loss of muscles (mild)

Red-green color blindness

Type of inheritance?

G6PD deficiency

Type of inheritance?

OTC deficiency

Type of inheritance?

All initial diseases named ONLY by initial

CPEO
LHON
MELAS
MERRF

Type of inheritence?

Mitochondrial

also

Kearns-Sayre syndrome
Leigh syndrome
Pearson syndrome

Coronary artery disease
Diabetes
Obesity
Alcoholism
Infantile autism
Cancer
Schizophrenia
Cleft lip/palate
Pyloric stenosis
Club foot
Spina bifida

EXAMPLES OF?

Amniocentesis

Chorionic Villus sampling (can do sooner, but more dangerous)

Nuchal translucency and maternal serum screening

Ultrasonography

Amniocentesis

Optimal Time?

Samples collected?

Tests what?

Conditions reflected?

Invasive?

• 15-17 weeks
• amniotic fluid and amniocytes
• alpha-fetoprotein (AFP) /DNA based testing/cytogenetic analysis
• Chromosomal abnormalities/genotype of selected genes/Trisomies (low AFP) or Neural tube disorder (High AFP)
• Yes (.5% fetal loss chance)

Chorionic Villus sampling (CVS)

Optimal Time?

Samples collected?

Tests what?

Conditions reflected?

Invasive?

• 10-11 weeks
• taking fetal trophoblastic tissue
• Cytogenetic analysis/dna based testing
• chromosomal abnormalities
• genotype status of selected genes
• Yes(1-1.5% fetal loss, risk of limb reduction)

Nuchal translucency and maternal serum screening

Optimal Time?

Samples collected?

Tests what?

Conditions reflected?

Invasive?

• 15-17 weeks
• maternal serum (taking mother's blood) and ultrasounds
• Nueral tube ( NT) / maternal AFP
• trisomies (low AFP)/ NTD (high AFP)/ chromosomal anomalies (NT)
• no risk

Ultrasonography

Optimal Time?

Samples collected?

Tests what?

Conditions reflected?

Invasive?

• 16-18 weeks
• visualization
• -
• Congenital malformation/NTD
• no risk

Erythrocyte life span?

produced where?

destroyed by?

120 days

bone marrow

resident macrophages (spleen, liver, bone marrow)

Development from stem cell to erythrocyte?

1 BFU-E can divide into __ RBCs?

divisions per blast stage?

Stem cell --> BFU-E -->series of blasts --> reticulocyte -->erythrocyte

1000s

3-5 rounds

Lifespan of reticulocyte?

where does it spend its time?

72 hours

48hrs in bone marrow, 24 hours in circulation

in cases of anemia, can be released early, 24/48

CFU-E/normoblast, Reticulocyte, Erythrocite (mature RBC)

present in bone marrow or blood?

CFU-E in bone marrow

Reticulocyte in bone marrow for 48, blood for 24

Erythrocite in blood.

So Reticulocytes are useful messengers of what is going on in bone marrow

1: Kidneys detect lower O2 in blood

2: Kidneys secrete EPO into blood in response

3: EPO stimulates erythropeiesis (by ligand binding)

4: Increased O2 carrying capacity of blood

5: Relieves initial stimulus that triggered EPO secretion

How does EPO exert its affects?

Increases division

Inhibits cell death of blast cells, so make more

increased Hb synthesis

Increased Fe absorption

Increased erythroid differentation

stimulated production and early release of reticulocytes

Recombinant EPO can be injected regularly to prevent severe anemia.

Folate (folic acid)

Vit B12

Dietary protein and Iron

abnormally low Hb concentration in whole blood samples

anemia is a SIGN of a disease, not a disease itself

5,000,000/microliter

5 is used in math

HGB?

what is it and avg?

hemoglobin concentration in whole blood

15g/dl

HCT

what is is and avg?

volume % of whole blood occupied by rbcs

45%

45 used in calculation not .45

RBC *3=HGB

HGB*3=HCT

in a normal person..

average volume or circulating RBS

80 and under microcytic

100 and up macrocytic

MCV= HCT/RBC  *10

amount of Hb in avg circulating erythrocyte

MCH= HGB/RBC   *10

What is MCHC and how to calculate it?

what does it identify?

concentration of HGB

MCHC= HGB/HCT   *100

normochromic/hypochromic rbcs

Anemia due to blood loss/premature destruction

body is ABLE to produce RBCs in response to EPO

Body unable to produce RBCs in spite of EPO increase

caused by decreased erythropoiesis

If HGB low, means what?

and then

if CR is decreased?

and then the MCV is low?

Anemia present

due to decreased erythropoiesis

if MCV is low, there are microcytic cells due to impaired HGB Synthesis

HGB low

and

CR low

and MCV high?

anemia present

decreased erythropoiesis

and the elevated MCV =macrocytic cells,

so due to limited DNA synthesis since cells aren't dividing

Decreased proteing synthesis.

most commonly caused by chronic iron deficiency.

inadequate protein in diet can contribute

macrocytic cells mean that the nucleotide supply is deficient.

the blast cell division time increases so the cells are larger

Most commonly due to B12 or folate deficiency

How much iron does the human body keep in storage?

in use?

How does the body get rid of Fe?

4 grams total, 1 g in storage, 3 in use

Body cannot promote iron loss, can only lose by bleeding. So body absorbs however much it loses by skin shedding (1-2 mg/day) to maintain homeostasis

Heme>>Ferrous Fe 2+ > Ferric Fe 3+ > Elemental iron Fe 0

Heme is mainly found in meat fish and seafood

5-35% of iron absorbed

Enhances it

Vitamin C reduces Fe 3 ferric to Fe2 ferrous. it can form complexes with ferrous iron. and iron complexes increase the bioavailability of ferrous iron

increases absorption by increasing gastric acid production increasing bioavailability

Form insoluble chelates decreasing mineral absorption.

high in cereal grains

decrease absorption

form insoluble chelates with minerals decreasing absorption

in Tea and Coffee

form insoluble chelates with Fe 2 and fe 3 iron

ex egg yolk

decreases it

chelate non heme iron

ex spinache. has a lot of iron, but only 5% is bioavailable because of high oxalate concentraion in spinache

Enterocytes of the duodenum and upper jejunem

surgical removal of any part of these will decrease iron absorption

Ferrous Fe2 when it is unbound

it catalyzes a highly destructiv hydroxyl radical OH in the fenton RXN

Fe2+H2O2 --> Fe3 +OH +OH

What binds to ferric iron?

What is this things name when bound to 0, 1, 2 irons?

Transferrin, can bind up to two Fe 3 atoms.

apotransferrin: not bound

monoferric transferrin: bound to 1

Diferric transferrin: bound to 2

Can't cross lipid bilayers directly, requires machinery for transport

All growing cells possess TfR, transferrin receptors, a plasma membrane protein that mediates iron uptake

What is the protein used to store iron?

What is protein used to store iron during iron overload?

ferritin.

is a 24 subunit protein, never H24L0 or H0L24 unless in pathological instances

Hemosiderin, another form of ferritin. contains 30% more stored iron than ferritin

.5 mg of iron / 1 ml of blood

so donating 500 ml of blood is 250 mg of iron

What is the laboratory value TIBC?

What is best test of iron stores?

Serum transferrin.

Serum ferritin is the best test of iron stores.

ferritin levels are found with ferritin too

low levels of iron

Ferritin is low because stores are depleted, and transferrin receptors are high because cells demand more iron

What is the most common coause of iron deficiency in adults?

toddlers?

Adolescent girls and premenopausal women?

pregnant women?

Acute or chronic blood loss (ie ulcers, tumors)

nutritional insufficiency

menstruation

increased requirement (3-4 mg of iron are transferred to fetus everyday)

early stages are asymptomatic

later stages include:

Koilonychias (concave nails)

Anisocytosis (inequality of RBC size)

Poikilocytosis (abnormal RBC shape)

Normochromic

Usually microcytic anemias involve hypochromic cells

both are macrocytic, but nonmegaloblatic are usually only 100-110MCV. dna synthesis is fine, etiology is usually alcoholoism, liver disease, medications.

Megaloblastic are 110-130 MCV usually, but up to 160. DNA synthesis is impaired, can have oval marcrocytes and hypersegmented neutrophils

Metabolism of Folate:

Folic acid gets to Tetrahydrofolate (THF)

nucleotide synthesis

Methylation rxns. folate acts as a carrier for methyl groups

is a structural analog of folic acid. inhibits dihydroflate reductase thus reducing the ability of the cell to recycle folate.

Used for killing cancer

homocysteine methyltransferase

involved in folate recycling

Methylmalonyl-coa-mutase

not used in folate recycling at all, good for identifying B12 or folate deficiency

SAMe

s-adenosylmethionine

Recycling of Folate

Methylation of cellular proteins and nucleic acids

Homocysteine is the enzyme that gets both of those going, and B12 is the coenzyme

If the folate recycling is compromised, what is the pathology?

If the methylation is compromised, what is the pathology?

Megaloblastic anemia

Peripheral neuropathy

Methylmalonic acid -->succynyl Coa

Methylmalonic levels will be elevated in cases of b12 deficiency but normal in folate deficiency

B12 Absorption

In the mouth, what is b12 bound to?

what enzyme is released?

b12 is still bound to dietary protein

R-Binder is secreted but does not bind yet

B12 absorption

What happens to B12 in the stomach?

what enzyme is releases?

Stomach is acidic, B12 is released from protein and binds to R-Binder.

intrinsic factor is released

b12 absorption

in the duodenum, what happens to B12-R binder complex?

There is a neutral pH, pancreatic proteases are secreted which degrade R binder

at this neutral pH, free B12 is able to bind to intrinsic factor

b12 absorption

in the ileum what happens to B12

the IF/B12 complex binds to a IF receptor on surface of ileal cells.

the complex is endocytosed and b12 released on basal side into circulation, bound to TRANSCOBALAMIN II

B12 absorption

in the portal blood what happens to b12

Transcobalamin II transports b12 to the tissues

In the tissues the transcobalaminII/B12 complex binds to cellular receptors and is endocytosed by cells

slow disease spanning decades usally age 50-80

simple treatments of b12

decreased stomach acid and its affect on B12 absorption?

what aspect of absorption would be affected?

decreases uptake

can happen by achlorhydria (decreased acid production by parietal cells) or use of antacids or proton pump inhibitors

pepsinogen to pepsin conversion would be decreased

a pocket forms in wall of small intenstine leadin gto stagnation of nutrent flow and increased bacterial growth (which absorbs b12)

surgery corrects this

DBIL test:

measures what

both unconjugated bilirubin and conjugated

measures 100% of CB and 10% of UCB

70% in spleen

15% in bone marrow

15% in tussues

resident macrophages in spleen and bone marrow:

what is the intermediate between Heme and unconjugated bilirubin?

Enzyme involved in Heme --> biliverdin?

biliverdin to bilirubin?

Heme oxygenase

biliverdin reductase

UCB/Albumin travels in blood to the liver, and only UCB enters the liver. what prevents UCB from getting back out of cell?

How is bilirubin conjugated?

What transports CB to bile duct?

In hepatocyte, UDP-glucoronyl transferase (UGT) adds 2 negative charges to bilirubin making is more hydrophilic

MRP2, a unidirection transporter

in the intestine, CB is metabolized by what?

producing what?

metabolized by colonic bacteria

urobilinogen

What % of urobilinogen is excreted?

what is its rxn?

What % is reabsorbed?

of that %, what % is reabsorbed by liver and waht % is excreted in urine?

90%

fecal urobilinogen is autooxidated into stercobilin(brown)

10% reabsorbed,

9% is reabsorbed by liver,

1% is excreted in urine as urobilin

Diazo rxn, gets TBIL and DBIL

Total-direct =indirect bilirubin

yellowish discoloration of skin nails, sclera caused by an INCREASE in amount of BILIRUBIN in the blood called hyperbilirubinemia

 not a disease, but a sign of a disease

neonatal

pre-hepatic

       caused by hemolytic anemia

hepatic

       caused by viral infection infecting integrity of liver

post-hepatic

       caused by bile duct obstruction

What causes neonatal jaundice?

50% of all neonates are jaundice within first 5 days of life because:

immature liver fails to produce adequate amounts of proteins necessary for bilirubin excretion

increased RBC turnover which results in elevated UCB since not enough enzymes to process it

blue light therapy. NOT UV LIGHT!

bilirubin is light sensitive, the blue light alters the conformation of UCB yielding more polar photoisomers. These isomers can be excreted in the urine or bile without further modification.

so it makes the hydrophobic UCB for ampipathic

Pre-hepatic jaundice

caused by? condition of liver?

hemolytic anemia, increased hemolysis of damaged/immature RBcs in spleen or bone marrow results in elevated UCB

No pathology of liver or duct

lab results will have IBIL increased due to increased UCB

Liver cells are damaged by viral infection.

UCB production normal, but conjugation is decreased

DBIL is still increased though beause CB leaks through leaky tight junctions

IBIL increased due to decreased conjugation

Post-hepatic jaundice caused by?

affects on test results

Bile duct obstruction results in blocked flow of CB from bile duct to intestine.

results in little or no urinobilogen (pale stool)

bile acid induced damage to liver cells causes leaky tight junctions. then there is a leakage of CB into circulation

DBIL is increased due to leaking CB

fecal/urinary urobilinogen is decreased due to CB flow obstruction

normal IBIL --> post-hepatic jaundice

normal DBIL--> pre-hepatic, liver undamaged so no leaky cells

decreased Urinary/fecal urobilinogen --> post hepatic, bile duct obstructed, no CB

In hepatic jaundice, everything is increased because of decreased conjugation AND leaky junctions. only thing normal is fecal

Pre-hepatic jaundice

liver is fine

if DBIL increased, and

urinary urobilinogen is...

increased?

decreased?

hepatic (can't reabsorb, so the 10% will go to urine)

post-hepatic

What is a point mutation?

types?

single base pair change in sequence of dna

Transitions: a puring replaced with a purine, a pyrimidine is replaced by a different pyrimidine

transversions: a purine is replaced by a pyrimidine and vice versa

if a point mutation occurs within a coding region, it can result in a change of a single amino acid.

Hemophilia B- reduces factor IX by 1/3 normal level

Tay-Sachs (some variants)- Hex A gene

Sickle cell- changes composition of b-globin. 1/12 blacks

    is a transversion point mutation

NF1 - stop codon into the NF1 coding region

B-thalassemia - decrease production of b-globin. many different kinds of pt mutations for this one

Tay-Sachs (most common variant)- small insertion of 4bp

Cystic Fibrosis - small deletion

diseases caused by large insertions/deletions?

Red-green blindness - large deletion in the cones (of the eye)

a-thalassemia- large deletion by a aberrent recombination

Charcot-Mari-Tooth : most common inherited neurologic disorder, large insertion caused by aberrent recombination. hammer toe

1000-2000000 bp polymorphism

Mendel

Principle of Segregation (1st Law)

Sexually reproducing organisms possess genes in pairs, and only one of each pair is transmitted to a particular offspring

Mendel

Principle of Independent Assortment (2nd Law)

Genes that reside on different loci are transmitted independently

later it would be shown that this law applies to only genes on different chromosomes or very far apart in same chromosome

what disease has ~90% of its cases from new mutations?

Achondroplasia

autosomal dominant, FGFR3 gene

gain of function, missense mutation

Homozygotes do not survive infancy (lethal mutation). this is true of all dominant diseases except?

hereditary hemochromatosis

what is its gene?

charcterstics? why is that bad?

HFE (think high iron(Fe))

iron overload. absorb 2-4 times the normal amount of iron. this leads to more of the Fenton rxn

pleitropy?

heterogeneity?

A single gene exerts its effects on multiple aspects of anatomy

where mutations at different loci produce same phenotype

SNRPN

this is the one coming from the father

ube3a

note, this is on chromosome 15

trinucleotide repeat expansion

ex for myotonic dystrophy

5-50 repeats =no symptoms

50-100= mild symptoms

100-1000 = full dystrophy

number of repeats increases in generations due to slippage of DNA polymerase

its believed that each person carries 5 recessive genes in heterozygous form, that would kill in homozygous form.

this is why consanguinity is bad

one of the 2 x chromosomes of females is randomly activated in every somatic cell.

x inactivation is random, UNLESS there is a gross structural abnormality of one of the x chromosomes in which the defective one is preferentially inactivated

this inactivation is permanent for all descendents of that cell

inactivated x chromosomes can be detected as a chromatin mass in somatic cells. women will have one less than the number of x chromosomes they have

ie. normal women will have 1 barr body. men 0.

Turner syndrom, XO, will have no barr bodies,

Quintuple x (XXXXX) will have 4

XIST

it is in the x inactivation center (XIC)

it is only found in females

1in10000 males

1in 100,000,000 females

no father -->son transmission

in the normal condition, 10% of purine is synthesized while 90% is recycled.

in the pathological condition, the decreased activity of HGPRT largely decreases the ability to recycle purine, Huge increase in uric acid production. The brain relies on this parthway so there is CNS damage

accounts for only .002% of striated muscle cell's protein mass. But it has a critical function in maintaining the structural integrity of the cells CYTOSKELETON

Duchenne's: most mutations are deletions that cause frameshifts leading to absence of dystrophin

Beckers: Usually result of in-frame deletion allowing for partial protein function

this is why Beckers is a milder form

Children use hands to stand up. this is a sign of muscle weakness and possibly duchennes MD

Heteroplasmy: when a daughter cell receives a mixture of mitochondria, some with a mutation and some without

Homoplasmy: when a daughter cell receives only a pure population of either normal mtDNA or mutated mtDNA

Mitochondrial diseases can show much variability due to heteroplasmy. the % of mutant mtDNA affects the expression

100%

eggs have 200000 mitochondria while sperm only has 200.

 mitochondrial inheritence is non-mendelian

Multifactorial inheritence

they are becoming a higher % of cases

No, there may be familial aggregation, but no clear inheritance pattern

also, it is not sex linked

quantitative.

bell shape curve

How are multifactorial qualitative traits explained?

Threshold model.

Everyone has liability for a disease but different thresholds, once you get to the threshold the trait appears

liability is composed of genetic and environmental factors

impossible to do.

recurrence risk can be determined by observing data

the more individuals affected in a family, the higher the recurrence risk

the less the degree of relationship with proband, the less the recurrence risk

the risk to relatives also varies with the severity of the condition of the proband

they are identical twins with the same genetics, so any differences are environmental

dizygotic or fraternal twins, are only as genetically similar as any other 2 siblings

What is concordance value?

what is the equation used to obtain an estimation of heritability of a disease?

Cmz and Cdz

if both members of a twin pair share a trait, they are said to be concordant, if not:discordant

h=2(Cmz-Cdz)

concordance itself says nothing about the heritability of a disease, the estimate of a genetic component only comes from comparing concordance of mz and dz twins

PKU, galactosemia and hypothyroidism

AZ screens 29 genetic disorders

there is a phenylalanine hydroxylase enzyme deficiency, which is required for conversion of phynylalanine to tyrosine.

because of the deficiency, both phenylalanine and phenylpyruvic acid build up, accumulate in the blood. they are toxic in high concentrations and produce IRREVERSABLE MENTAL RETARDATION by 1-month of age

One of the products of the rxn inhibited by PAH deficiency, is melanin (the other is adrenaline)

The products are decreased so less melanin

most women with PKU have given up diet therapy by child bearing which has no ill effects on them, but can cause irreperable harm to the fetus, causing brain damage

preimplantation genetic diagnosis (PGD)

couples with high risk for a disease can do this

Take a single cell from the 8-cell blastomere produced by in vitro fertilization and is tested by the PCR (polymerase chain reaction). if healthy, its reimplanted.

What do high levels of fetal AFP correlate to?

low levels?

increased risk of neural tube disorders

Increased risk of trisomies

at 10-11 weeks, chrionic villus sampling (CVS)

ultrasonography, 16-18 weeks

replacing the standard maternal AFP(a-Fetoprotein)

tests anencephaly, spina bifida, down syndrome

by measuring AFP, hCG and estriol

What is the leading known cause of mental retardation?

as well as leaading cause of pregnancy loss?

chromosome abnormalities

ordered display of 23 pairs of chromosomes.

first classified by size and then position of centromere

What is a p-arm?

q-arm?

p arm(p stands for petite) is always oriented at the top

q at the bottom and is the long end

metacentric chromosomes?

acrocentric chomosomes?

submetacentric chromosomes?

centromere occurs near middle of chromosome

centromere is near telomere (shorter p arm), and looks different, has a stalk and satelite

centromere resides somewhere between telomore and the middle

polyploidy?

tetraploidy?

Monoploidy?

gain of one or more entire chromosome sets

triploidy is 3 copies, so 69 chromosomes

tetraploidy refers to 4 copies of each. this is a lethal condition, only a few live births ever

monoploidy is loss of entire set, NOT seen in humans

what is aneuploidy?

cause?

gain or loss of one chromosome

monosomies and trisomies are usually caused by nondisjunction (failure of 2 members of a chromosome to disjoin or or seperate) during meiosis I or II

Autosomes 13, 18, 21

these have the fewest genes of the chromosomes so can probably handle the excess material better

What is trisomy 21?

Cause and origin of?

47, XY +21 or 47 XX +21

Down Syndrome

95% of trisomy 21 cases contributed to the mother

is the most compatible with live birth

only risk factor is advanced maternal age

Edward syndrome

47 XX/XY +18

only 10% babies survive past a year, 50% a month

This is the most common, but more lethal, so not as many born as down syndrome

also 95% due to nondisjunction in the mother

Patau syndrome

47 xx/xy +13

same, 95% nondisjunction caused by mom

Turner, missing an x-chromosome, an abnormality of sex chromosome tolerated more than on autosomes

Klinefelter

the fact that some phenotype is exhibited is due to incomplete x inactivation

x and y chromosomes pair and undergo recombination. just proximal to the pseudoautosomal region there is a gene called SRY, which initiates male development.

In an aberrent recombination, the SRY gets sent to the x chromosome

what are chromosomal translocations?

what are the two kinds?

interchange of genetic material between chromosomes

Reciprocal translocation: chromosomes break on 2 diff chromosomes, then they switch places

      generally no phenotype as there is no LOSS of material

Robertsonian translocation: involve only acrocentric chromosomes, 13 14 15 21 22, and involves loss of short arms of two acrocentric chromosomes and fusion of long arms at the centromere

      These offspring have one fewer chromosome, ie have a chromosome like t(14q21q). usually exhibit deletions or duplications

What occurs in the G1 phase?

pretein synthesis, preparing for one cell to become 2, so the cell begins replicating non-chromosomal contents

(mitosis)

cell division, the duplicated DNA condenses into mitotic chromosomes and then daughter cells

G1/ G2

the cell is not actively replicating or dividing DNA

They are more active than G0, which is not preparing for cell division

interphase is all steps but mitosis

A signal from a mitogen (growth factor) to enter a new round of cell division, without it, the cell enters G0

muscle and nerve cells

others will continue to divide as long as they receive growth factor

What are the cyclins and CDKs for the following sections

G1 early  

G1 late

G1/S

S/G2

M

Cyclin D     CDK 4/6

Cyclin E     CDK2

Cyclin A     CDK2

Cyclin A     Cdc2

Cyclin B     Cdc2

CDKs must be bound to a cyclin to have activity

Mitogen (growth factor) bind to receptors on surface of cell and initiate phosphorylation cascade through GTPase Ras. then goes to the MAP kinase which increases synthesis of actiity of transcription factor MYC. MYC increases expression of Cyclin D

Mitogen -> Ras ->MAP ->MYC -> Cyclin D

cell must cross Restriction (R) point, Cyclin D levels need to be high to stimulate CDK 4/6 and must also have growth factor mitogen. After this Cyclin E/CDK2 must kick in to help the cell pass the restriction point.

these proteins work together to phosphorylate Rb...

Rb must be hyperphosphorylated to unbind from E2F which will go on to act as a transciption factor, leading cell to S-phase..

Cyclin D HYPOphosphorylates Rb

Ciclin E then HYPERphosphorylates Rb

p21

p16 gets Cyclin D/CDK4 6

these are called CDKI (inhibitors)

all of them

p21 can also block cell at R point by inhibiting cylcin E/CDK2 which will prevent hyperphosphorylation of Rb

what kinds of stress is p16 induced during?

p21?

p16 is induced in times of environmental stress, i.e starvation

p21 is induced following DNA damage

abnormal proliferation of cells

not regulated, replicating constantly

where do carcinomas arise from?

sarcomas?

lymphomas/leukemias?

epithelial cells. 90% of tumors are carcinomas

ex: lung prostate breast skin colon

supporting tissues: rare 1%

ex blood vessels, adipose, muscle, bone

lymphatic and blood origin

lymphoma is a solid mass of white blood cells

leukemia is cancer in which malignant blood cells proliferate to blood stream

a single progenitor cell gives rise to subpopulation of identical cells

takes years, cells acquire many additional mutations to progress to malignancy

Cancer is a progressive accumulation, otherwise cancer should be independent of age

Sulf sufficiency in growth signals

Loss of differentiation

Tissue invasion and metastasis

Sustained angiogenesis

Limitless replicative potention

Evading apoptosis

Cancer cells secrete proteases called Matrix Metalloproteinases (MMPs)

the tumor and stroma evolve together, gives tumor cells ability to invade and metastasize (break through basal lamina)

invade local tisue and vessels

move through circulation

leave vesse

establish new colonies at distant site

Liver (Portal system)

so stomach and colon cancer often ends up in liver

this is because cancer cells are larger than RBCs so get caught in first capillary bed they end up in

bone

how do tumor cells use angiogenesis?

either increased cell divisionand normal apoptosis

or

normal cell division and decreased apoptosis

both lead to a tumor

what is a tumore initiator?

tumor promotor?

initiator: single application does not cause cancer but does cause latent genetic damage

ie. chemical or environmental

promotor: nonmutagenic, but repeated exposure to areas treated with tumor initiator will cause cancer

initiation phase:   cell receives a mutation that gives it the potential for abnormal growth

promotion phase, the initiated cell is stimulated by external factors

progression phase:   cell has sustained enough mutations that it no longer needs external factors (such as growth factors) to proliferate

example of a virus promoting cancer?

how does it do this?

HPV, human papilloma virus

HPV has two proteins, E6 and E7

E6 destroys p53, E7 liberate E2F

oncogenes (found in most cancers)

they are a mutated version of a proto-oncogene(NOT mutated), can bypass restriction checkpoints

tumor suppressors

when inactivated, tumor cells arise

Oncogen mutations:

RTK mutation?

Receptor tyrosine kinases RTK, are normally only activated when a growth factor binds.

1: truncated ones do not need a ligand, they continually send messages

2: other cases, amplification results in too many receptors, so even small amounts of ligand signal cell growth

what happens to Ras so it cannot stop cell division in tumors?

p53

50% of tumors have mutation or deletion of p53

what are the 2 forms of Retinoblastoma?

Familial- occurs in family clusters, affected children frequently develop tumors in both eyes, because already have one mutation

sporadic - no family history, usually only develop in one eye due to its random mutation

hereditary defect in p53 gene

these individuals have a 90% chance of developing cancer, but no specific cancer dominates

some get multiple cancers in succession

also called lynch syndrom

inability to correct mistakes made during DNA replication. 90% of individuals with an HNPCC mutation will develop cancer

inability to repair DNA damage from uv radiation

skin cancer develops