genetics_block_3_20140408204917 Flashcards
What are the 2 classes of proteins?
- Housekeeping Proteins
* Tissue-Specific Specialty Proteins
What are houskeeping proteins?
They are fundamental to maintenance of structure and function
What are tissue-specific specialty proteins?
have unique functions
Where dotissue-specific specialty proteins get made?
In 1 or different cells
Where do we find houskeeping genes?
in every cell
What are the two broad generalizations that can be made about the site of a disease and the site of a proteins expression?
- A mutation in a tissue-specific protein produces a disease restricted to that tissue
- housekeeping genes are in all cells; but a mutation in one will not cause all others to express pathologically.
What are the 2 reasons why clinical effects of mutations in housekeeping proteins are frequentlylimited to one or a few tissues?
- Genetic redundancy A specific tissue may be affected because the protein inquestion is expressed abundantly there and serves a specialty function
How do you explain clinical heterogeneity of genetic disease using genetic variation?
- allelic heterogeneity-mutation:
- different alleles of a single gene can be compared with phenotypes of variable severity
- locus heterogeneity-mutation:
- A mutation in a different gene can cause a similar but distinguishible phenotype.
- Modifier genes:
- mutations in a separate gene causes the samemutation in another gene to have different effects.
What is Phenylketonuria (PKU)?
Is an inherited error in metabolism caused by deficiency in Phenylalanine hydroxase (PAH). (Phenylalanine builds up)
What symptoms can be seen in loss of Phenylalanine hydroxylase?
- mental retardation
- organ damage
- unusual posture
- Musky odor in diaper from Phenylpyruvic Acid
Classic PKU is what kind of inheritance?
Autosoma Recessive
How many alleles are mutated in the PAH gene in PKU?
both alleles are mutated in chromosome 12the one with more milder phenotype predominates
What does Phenylalanine hydroxylase do in the body?
converts phenylalanine to tyrosine by hydroxilating the phenolic ring
What is the mild form of PKU?
hyperphenylalanemia
Apart from PAH, what do the other 4 genes that cause PKU do?
production or recycling of tetrahydrobiopterin (BH4)
What is the normal plasma level of phenylalanine?
What does BH4do with PAH?
Its a cofactor for:Tyrosine —–> Cathecolamine ——-> NE & EpinephrinTryptophan ——-> 5-HT (Serotonin)
What doBH4-deficient patients develop?
profound neurological problems
What is BH4used for?
it is a cofactor for PAHit is a cofactor for Tryptophan hydroxylase and tyrosene hydroxilaseTyrosine————–>Catecholaminas————-> NE & ETryptophan —————–> 5-HT(Serotonin)
True of FalsePatients with PKU are usually homozygotes?
False - compound heterozygotes
What are the Clinical Features of PKU?
- developmental delay in infancy
- microcephaly
- seizures
- hyperactivity
- behavioral disturbances
- musky smell in diaper (phenylalanine metabolized to phenylperuvic acid which is peed)
How do you treat PKU?
phenylalanine diets (avoid proteins, dairy & eggs) and supplements of BH4
What happens if PKU is left untreated?
Severe Mental Retardation
What is Maternal Phenylketonuria?
It is a type of PKU that affects the unborn childIt attacks the developing CNS
What are the symptoms of Maternal Phenylketonuria?
- microcephaly
- mental retardation
- heart malformations
- growth impairment
What type of inheritance do most of the Lysosomal diseases have?
Autosomal Recessive
What is the treatment of lysosomal storage disease?
ERT: Enzyme Replacement Therapy
What happens with lysosomes in lysosomal storage disease?
They accumulate substrate inside lysosome and it leads to cellular dysfunction and cell death.
What kind of disease is Tay-Sachs?
Lysosomal Storage Disease
What kind of disease is Gauchers Disease?
Lysosomal Storage Disease
What kind of disease is MPS I (Mucopolysaccharidoses) disease?
Lysosomal Storage DiseaseType I = Hurler’s
What kind of disease is MPS II (Mucopolysaccharidoses) disease?
Lysosomal Storage DiseaseType II = Hunters
What is another name for MPS I (Mucopolysaccharidoses) disease?
Hurler’s
What other name does MPS II (Mucopolysaccharidoses) disease have?
Hunter’s
What is happening with Tay Sachs disease?
Lysosomes cannot degrade GM2Gangliosides
What enzyme is deficient in Tay Sachs?
Ubuquitous Hexosaminidase A Enzyme
With what type of inheritance is ubiquitous hexosaminidase A enzyme related?
with Autosomal Recessive inheritance
What body part is mainly affected clinically with Tay Sachs?
The brain since it is the predominantsite of GM2 ganglioside synthesis
What are the 3 components of the acitive Hex A enzyme?
- HexA
- HexB
- Sandoff activator protein
What disease symptoms are clinically identical to Tay Sachs?
Sandhoff diseaseHex A needs Sandhoff Activator Protein thus if absent, identical symptoms of Tay Sach are to be seen.
What does the activator protein of the HexA enzyme do?
binds the ganglioside substrate and present it to the enzyme. NANA (N-acetyl neuraminic acid)
If there is a 4-base insertion on HexA, what kind of mutation is present? and what are the bases and where are they located?
A frameshift mutation. TATC insertion on Exon 11
In what population will we see Tay Sachsm more predominantly?
In Ashkenazi Jews as usual
What will not be made if there is a 4-base insertion/frameshift?
HexA will not be made
In Tay Sachs, when will infants begin to show signs of the disease?
first 3-6 months they look normal, afterwards they show signs of neurological deterioration. Usually death @ 2-4yrs
What is a cherry red spot in the retina a sign off? and what disease presents with this symptom?
Tay Sachs and it means that there is accumulation of storage material in the retina
Later onset of Tay Sach variants will manifest with these symptoms…
- Lower motor neuron dysfunction
- Ataxia————————————————–These occur because of spinocerebellar degeneration
- Psychosis in 1/3 of patients
Later onset variants will manifest with symtoms except for?
vision and Intelligence that will remain normal
Where do GAG’s or Mucopolissaccharide chains accumulate?
Lysosome
What are GAG’s made off?
Long dissacharide repeating chains with two sugar molecules
GAG’s orMucopolysaccharide Disorders accumulate in lysosomes of tissues and cause what type of deformities?
Skeletal and extracellular matrix deformities
What type of inheritance is Hurler’s Syndrome?
Autosomal Recessive (its lysosomal)
What is deficient in Hurler’s Syndrome?
alpha-L-iduronidase
How does Hurler’s present?
- corneal clouding
- skeletal abnormalities
- death by cardiorespiratory failure
- by 3 years there is linear growth
- hearing loss
- profound mental retardation
- coarse faciesRule of L: HurLe’s, alpha-L-iduronidae, corneaL cLouding, hearing Loss
What is I-Cell disease?
Lysosomal storage diseaseDefect in enzyme that transfers phosphate group to mannose residues in the Golgi.or…in fancy world:”There is a N-acetylglucosamine-1-phosphotransferase deficiency leading to deficiency in protein trafficking”.
How do patients with I-Cell present?
unusual facial featuresskeletal changesMental retardationexcess acid hydrolases in body fluids
What is Classic Homocystinuria?
Mainly it is a deficiency in enzyme cystathionine ß-synthase (Vit. B-6)can also occur with deficiency of methionine synthase (folate = Vit. B-12)
What inheritance is Homocystinuria?
Autosomal Recessive
What are some of the symptoms that patients with homocystinuria will present with?
mental retardationosteoporosis oflong bonesDislocation of the Lensthromboembolism of the veins & arteries
6 causes of homocystinuria
Classic = defective cystathionine synthasedecrease in Methyl-H4-folate reductase: impairing methionine synthasedefects in the intracellular metabolism ofcobalamins lead to a secondary decrease in the synthesis of methyl-cobalamin (methyl-B12) and thus in the function of methioninesynthase.Defect in cobalamine absorption and transportation
What is alpha-1-antitrypsin deficiency?
deficiency ina1AT secreted by the liver into plasma. It inhbits elastase(the function of elastase is to degrade alveolar walls causing COPD)Elastase is secreted by neutrophil in the respiratory track
What type of inheritance isalpha-1-antitrypsin deficiency?
Autosomal Recessive
What happens with the Z allele inalpha-1-antitrypsin deficiency?
it is the most common
What do homozygotes with Z/Z inalpha-1-antitrypsin deficiency develop?
17% develop neonatal jaundice & 20% of those will develop cirrhosis
With what does the Z protein tend to aggregate with?
aggregates with the RER of hepatocytes which causes formation of bead-like necklaces of mutant alpha-1-antitrypsin polymers.It results in increased elastase activity in lungs (alveoli elastin loss)
What is the effect of smoking in alpha-1-antitrypsin?
It oxidizes methionine causing a decrease in affinity of alpha-1-antitrypsin for elastase by 2,000 folds.
What type of disease is I-Cell?
Lysosomal storage disease
What causes Acute Intermittent Porphyria?
Its caused by mutation in the gene encoding forporphobilinogen deaminase (PBGD)
What kind of inheritance is Acute Intermittent Porphyria?
Autosomal Dominant
What causes Acute Intermittent Porphyria to show symptoms?
When heme levels drop in hepatocytes
How is Acute Intermittent Porphyria exacerbated?
Barbituates (Drugs)Steroidsreducing dietssurgery
What happens if exposed to precipitating factors?
increase of synthesis of P450, dropping heme levels and reducing the heme synthetic pathway also, via feedback inhibition of heme onδ-amino-levulinic acid (ALA) synthetase
What is the clinical presentation of Acute Intermittent Porphyria?
acute episodes of a variety of gastrointestinal and neuropathicsymptoms; between episodes, the patient is healthyAbdominal pain is the most common symptom (Vomiting)Mental disturbance: (Confusion, Emotional upset, Hallucinations and psychosis)
What is Familial Hypercholesterolemia?
is oneof the type 2 familial hyperlipoproteinemias characterized by elevationof plasma cholesterol carried by LDL.
What is the inheritance of Familialhypercholesterolemia?
Autosomal Dominant
What is damaged in Familialhypercholesterolemia?
Mainly LDL receptors4 possible proteins may cause Hypercholesterolemia or Hyperlipidemia
What are the four proteins associated with Familialhypercholesterolemia?
- LDL receptor mutation: Chromosome 19 Mutations in the LDL receptor binding domain of ApoB-100: Chromosome 2
- impairs LDL binding to its receptor by ApoB-100 PCSK9 protease activity leads to degradation of the LDL receptor: Ch 1 Mutation in ARH adaptor protein, links the receptor to the endocytic machinery of the coated pit causing clustering of the LDL receptor-ApoB-100 complex in clathrin-coated pits: Ch 1
What is the most important gene abnormality in FamilialHypercholesterolemia? Why?
PCSK9 protease geneMutation of this gene will cause the disease but some variants lower the plasma LDL cholesterol level giving some protection from coronary hearts disease
What are some symptoms of Familial Hypercholesterolemia?
premature heart diseasexanthomas (homozygous for the gene)arcus corneae (fat deposits in cornea)
What is deficient in Cystic Fibrosis?
pancreatic enzymes
How do you restore normal digestion in Cystic Fibrosis?
pancreatic enzyme supplement
What is wrong with Cystic Fibrosis males?
They lack a vas deferens and therefore are infertile
How is the stool of CF patients?
Greasy, lighter in color,
What is the major cause of Cystic Fibrosis?
Psudomonas aeruginosa
What are the 2 muscular dystrophies resulting from defects in dystrophin gene?
- Duchenne
* Beckers
What type of inheritance is Duchenne and Beckers?
X-Linked
What are the clinical features of Duchenne muscular dystrophy?
gower maneuvers High lvs of creatinine kinase (CK)
- boys are normal first year of life
- slow developing progression of muscle weakness
- gait
- lumbar lordosis
- Wheelchair bound by age 12 joint contracture pseudohyperthrophy: increase in the size of calf (calf muscles replaced by fat and fibrous connective tissue)
Greatly elevated Creatinine levels may indicate what disease?
Duchenne Muscle Dystrophy
What are the clinical features of Becker’s Muscle Dystrophy?
sames as Duchennes but at a slower onset
Genetically, Duchenne and Becker’s exemplify what?
Allelic Heterogeneity (different mutation same gene)
Deletions in the codon for Duchenne MD is due to what?
a frameshift mutation
Deletions in the codon for Becker’s MD is caused by?
In-frame mutation
What is the frequency for DMD and Becker’s?
60%
What is Ehrler-Danlos Syndrome?
genetic defect in collagen structure, synthesis, secretion,or degradation.
What is the clinical presentation of Ehrler-Danlos?
HypermobilityHyperelasticitySkin fragilityTendency to bleedAortic AneurysmCigarette Paper skin
What do Type 1 and Typer 2 Ehrler-Danlos have in common?
The mutations are linked to loci that contain the COL5A1 gene orCOL5A2 genes; encoding the alpha chains of type V collagen,leading to defective type V collagen
What is the frequency of Type 1 and 2 Ehrler-Danlos Syndrome?
1/30,000
What is the frequency of Type 3 Ehrler-Danlos Syndrome and how does it presents?
1/5,000Patient may have arterial or uterine rupture
What type of collagen is associated with type 4 EDS and where would you find it?
Reticular Type 3 CollagenFound in vasculature and skin
What is the deficiency found in type 6 EDS?
Lysyl Hydroxylase
Whats wrong in Type 7 EDS?
Can’t turn procollagen to collagen
With what can we associate type 8 EDS?
Dermatosporaxsisskin fragility
Of the two dystrophies resulting from a mutation in the dystrophin gene, which is more severe?
Duchenne: more severe/lack of dystrophinBeckers: less severe
What is the defect gene in Ehrler-Danlos Syndrome?
Col3A1
What is the major risk with type 3 Ehrler-Danlos Syndrome?
Death
What is Osteogenesis Imperfecta?
is a group of inherited disorders that predispose to easy fracturing of bones, even with little trauma, and to skeletal deformity
What are the 2 broad classes of mutations in alpha chains of Type 1 collagen for Osteogenesis Imperfecta?
- Null Mutation
* Missense Glycine Substitution Mutation
What is a null mutation?
Reduces the amount of type 1 collagen made
Give 2 examples of Null mutations
- promoter mutation
* splice signal mutation
What is aMissense Glycine Substitution Mutations?
Mutations that alter the structure of type 1 collagen*Mutation is worse the closer to the C-terminus of the alpha chain
How do you get the more severe form of Osteogenesis Imperfecta II?
If a Gly is substituted with a Glu, Ala, Val, Asp, or Arg in the C-terminal 2/3 of the molecule
How do you get the more severe form of Osteogenesis Imperfecta I?
substitutions in the N-terminal ¼ of the protein.
In what type of Osteogenesis Imperfecta does the fetus die in utero?
Type 2
Describe clinical features of Osteogenesis Imperfecta I.
- Blue Sclera
- Bone deformity is absent or minimal
- Collagen structure is normal but in few amounts
Describe Type II Osteogenesis Imperfecta.
It is the most severeLethal in/after birthCollagen improperly formedIt is a new mutation (recurrence in the family is low)
Describe Type III Osteogenesis Imperfecta.
Blue ScleraProgressive bone deformity (Severe)Collagen is improperly formedSpinal curvaturehearing loss
Describe Type 4 Osteogenesis Imperfecta.
White ScleraMild to moderate bone deformityBarrel shaped esphagusCollagen is improperly formed
What type of inheritance is Alzheimer’s disease?
Autosomal Dominant
How common is Alzheimer’s in women?
twice as common
What is the phenotype of Alzheimers?
Clinical features are characterized by a progressive deterioration of memory and of higher cognitive functions, such as reasoning, in addition to behavioral changes
What happens if there is a mutation in PSEN1 or PSEN2?
Mutations in PSEN1 or PSEN2 can lead to a gain of functionresulting in increased Ab42 peptide production
For what is PSEN 1 (Presenilin 1) required?
its required for gamma-secretase cleavage of Beta Amyloid Precursor Protein (BAPP) derivatives.- could beacritical cofactor protein of γ-secretase.
What does presenilin 2 (PSEN 2) do?
Same as PSEN 1
What does APOE (Alipoprotein E) used for?
It is a necessary component for binding VLDLs to their receptors
Why is thee4 allele a major risk factor for?
Developing Alzheimer’s Disease
Why do diseases of mitochondrial DNA occur?
defects of single genes
How are mitochondrial diseases inherited? can males pass the disease?
They are inherited from the mother and males cannot pass it.
What are the 3 types of mutations for mitochondrial diseases?
–Missense mutations in coding regions of genes that alter the activity of oxidative phosphorylation proteins. Point mutations in rRNA and tRNA genes that impairtranslation of mitochondrial proteins. Rearrangements that cause deletions and duplications inmtDNA.
What is MELAS?
It stands for Mitochondrial Encephalomyopathy, Lactic Acidosis and Stroke-like Episodes
What is MELAS?
•MELAS is a condition that affects many of the body’s systems, especially the brain, nervous system (encephalo-) and muscles (myopathy)
What kind of disease is MELAS?
Mitochondrial Disease
What do patients with MELAS have an accumulation of?
They have Lactic Acid buildup or Lactic Acidosis
Patients with MELAS will suffer from a repetition of this symptom….
Stroke-like symptoms that may damage the brain
What is Myoclonic Epilepsy with Ragged-Red Fibers (MERRF)?
is a multisystem disorder characterized by myoclonus, which is often thefirst symptom, followed by generalized epilepsy, ataxia, weakness, anddementia.
When does the onset of MERRF occur?
childhood
What are the 4 features to clinically diagnose MERRF?
- Myoclonus Generalized epilepsy Ataxia Ragged red fibers(RRF) in the muscle biopsy
What is the most common mutation found inover 80% of affected MERRF individuals?
an A-to-G transition at nucleotide 8344
What gene that makestRNALys is thegene most commonly associated with MERRF?
The mtDNA gene
In MERRF, since mutations are usually present in all tissues, how are these mutations detected?
They are detectedin mtDNA from blood leukocytes.
What is anAutosomally transmitted deletions in mtDNA?
It is a syndrome caused by mutations in two nuclear genes
What is the phenotype forAutosomally transmitted deletions in mtDNA?
It resembles chronic progressive external ophthalmoplegia(CPEO) (paralisys of eye muscles)
What ismtDNA depletion syndrome?
disease involvingmutations in any of six nuclear genes that lead to a reduction in thenumber of copies of mtDNA in various tissues.
How ismtDNA depletion syndrome inherited?
Autosomal Dominant
What is so special aboutKearns-Sayre syndrome and Pearson syndrome?
They are mitochondrial diseases that are not typically maternally inherited due to heteroplasmy
Leber hereditary optic neuropathy is homoplasmic or heteroplasmic?
homoplasmic
Is MERRF homoplasmic or heteroplasmic?
heteroplasmic
What is the most common mitochondrial DNA mutation ?
3243A>G (normal nucleotide = A, which is substituted by G) in the tRNAleu(UUR) gene
To what different diseases can3243 A>G (normal nucleotide = A, which is substituted by G) in the tRNAleu(UUR) gene lead?
- diabetes anddeafness
* chronic progressive externalophthalmoplegia (CPEO) cardio-myopathy or myopathy
Name 1 example of a mitochondrial disease that is multifactorial.
Leber hereditary optic neuropathy
What is Leber’s hereditary optic neuropathy?
Its the rapid, painless bilateral lossof central vision due to optic nerve atrophy in young adults
In LHON, in what sex is there increased penetrance?
Males have a 50%
In LHON, what increases the chances of blindness?
Alcohol and tobacco use
This disease is a trinucleotide repeat of CGG
Fragile X Syndrome
This disease is a trinucleotide repeat of CAG
Huntingtons Disease
This disease is a trinucleotide repeat of GAA.
Friedreich Ataxia
This disease is a trinucleotide repeat of CTG
Myotonic dystrophy 1
What is anticipation?
refers to a pattern of inheritance in whichindividuals in the most recent generations of thepedigree develop the disease at an earlier age and/orwith greater severity as it is transmitted through afamily.
What causes anticipation?
the intergenerational expansion of therepeats upon passage from one generation to the next
What causes the slipped mispairing mechanism thought to underlie the expansion of unstable repeats?
an insertion thatoccurs when the newly synthesized strand aberrantly dissociates from the template strand during replication synthesis.Once DNA synthesis is resumed, the misaligned molecule will contain one or more extra copies of the repeat
What are the 3 pathological mechanisms that occur in unstable repeat expansions?
Class 1 Diseases due to the expansion of noncoding repeats that cause a loss of protein function Class 2 Disorders resulting from expansions of noncoding repeatsthat confer novel properties on the RNAClass 3
* Diseases due to repeat expansion of a codon
What is impaired in class 1 of the pathologic mechanisms in unstable repeat diseases?
There is impaired transcription of pre-mrna of affected gene
What is Fragile X Syndrome?
Occurs when CGG repeats exceed 200, it triggers excessivemethylation of cytosines in the promoter, thus silencingtranscription from the gene.
When do you have the pre-mutation of Fragile X?
you get FXTAS when you have 60-200 CGG repeats
How does FTAX manifests?
It manifestsas late-onset, progressive cerebellar ataxia and intention tremor dueto the formation of intranuclear neuronal inclusions.
What does FMRP regulate?
regulates the translation of proteins required forthe formation of synapses
What is Freidreich Ataxia?
is the most common inherited spinocerebellar ataxia
How is Freidreich Ataxia inherited?
Autosomal Recessive
What 2 symptoms follow Freidreich Ataxia?
- Cardiomyopathy
* Type 2 Diabetes
What is wrong in Freidreich Ataxia?
There is a defect is in expression of the frataxin gene due to expansionof GAA in intron 1, the GAA repeats result in the inhibitionof transcriptional elongation.
Where can Frataxin be found?
In the mitochondria, it is a mitochondrial protein
What does Frataxin do in the mitochondria?
It is involved with iron metabolism
What happens if Frataxin activity is lost?
there will be:
- increased levels of mitochondrial iron
- impaired heme synthesis
- reduced activity of Fe-S-containing proteins (complexes 1-3 of mitochondrial respiratory transport chain)
What is Myotonic Dystrophy 1?
condition with the mostpleiotropic phenotype of all the unstable repeat expansion disorders
What are some of the clinical features of Myotonic Dystrophy-1?
Myotonia (muscle weakness) Cardiac conduction defects Testicular atrophy Insulin resistance
What is the mutated gene in Myotonic Dystrophy-1?
DMPK
What does DMPK code for?
a protein kinase
In Myotonic Dystrophy, there is a repetition of a trinucleotide…what is this trinucleotide? what is the mutated level for this trinucleotide?
CTG in 3’ UTRmore than 50 = mutation
How does the pathogenesis of Myotonic Dystrophy-1 result?
•esult from the binding ofRNA-binding proteins to the CUG repeats
What kind of inheritance is Huntington’s Disease?
Autosomal Dominant
What are some of the clinical presentations of Huntingtons’s Disease?
- Chorea
- loss of cognition
- psychiatric abnormalities
What is the trinucleotide repeat for Huntington’s Disease?
CAG
Why is the expansion of the trinucleotide so special in Huntington’s Disease?
Becuase it is a novel function of the huntingtin gene.
Name a striking cellular hallmark of AD.
the presence of insolubleaggregates of the mutant protein in nuclear inclusionsThese inclusions may actually be protective as it is the solublenonaggregated form of the mutant protein that promotes abnormalinteractions between the polyglutamine tract and a number oftranscriptional regulators to alter the transcription of manygenes.
Why does deficient genetic treatment occur?
gene is not identified or pathogenesis is not understood
- the mutant locus is unknown prediagnostic fetal damage
- the disease occurs too early in the development severe phenotypes are less amenable to intervention
- if patient is too severe there may be no longer a viable good protein.
How do you treat Familial Hypercholesterolemia heterozygotes?
combined use of:
- cholestyramine: abile acid-binding resin
- HMG CoA reductase: an inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A reductase
What is the most common cause of Vitamin-responsive enzyme defects?
due to mutations thatreduce the normal affinity (top) of the enzyme protein (apoenzyme) for the cofactor needed to activate it
What does PTC treatment use?
Ataluren
What does Ataluren do?
It is anew drug designed to enable the formation of a functioning protein in patients with genetic disorders due a nonsense mutation
What is protein augmentation?
it is used inproteins whose principal site of action is in theplasma or extracellular fluid•
What disease is treated with protein augmentation?
Hemophilia and Alpha-1-Antitrypsin Deficiency
How is protein augmentation used in Hemophiliacs?
Patients are treated with aninfusion with plasma fractionsenriched for factor VIII; replacing an extracellular protein: a1-antitrypsindeficiency
What is Adenosine Deaminase Deficiency (ADA deficiency)?
Is a deficiency that results in an accumulation of deoxyadenosine, which, in turn, leads to: a build up of dATP in all cells, which inhibits ribonucleotide reductase and prevents DNA synthesis, so cells are unable to divide
What does Adenosine Deaminase do?
It converts adenosine to inosine and deoxyadenosice to deoxyinosine.
What are the most susceptible cells to ADA deficiency? and why?
T cells and B cells, because they are among the most mitotically active cells.
How are patients with ADA deficiency treated?
With bone marrow transplantation & ERT
What is Gaucher’s Disease?
Its alysosomal storage disorder due to a deficiency of glucocerebrosidase
What inheritance is Gaucher’s Disease?
Autosomal Recessive
What population is most prevalent to Gaucher’s Disease?
Ashkenazi Jews
What gene is affected in Gaucher’s disease?
Lysosomal Cerebrosidase
What kind of gene is lysosomal cerebrosidase?
housekeeping gene
In Gauchers diseaseIn what organelle does glucerebrosidase accumulate? What type of cell is mostly affected?
It accumulates in Lysosomes and usually in Macrophages
What does the accumulation of glucocerebrosides in lysosomes of macrophages cause?
enlargement of the liver and spleen; also replacement of the bone marrow by lipid-laden macrophages.Compromises production of RBC’s and platelets leading to anemia and thrombocytopenia
What is Enzyme Replacement Therapy?
Is atargeted augmentation of an intracellular enzyme
What is Decitabine use for and how does it work?
Is use for Sickel Cell patients. Its function is to decrease the methylation that occurs on CpG.
What is deficient in Krabbe Disease?
B-galactocerebrosidase
What is the early and late onset of Krabbe?
Early: first month and die before age 2Late: 6 months and die before age 3
What is nuclear transplantation?
Transfer of diploid nucleus from an adult donor somatic cell into an oocyte cytoplasm to generate a cloned embryo.
What is reproductive cloning?
Reimplanting an embryo obtained by nuclear transplantation into the uterus of a surrogate mother.
What is therapeutic cloning?
Use of embryonic stem cells to form differentiated cell types of the body in culture i.e. grow an ear or kidney etc…
Why is cord blood better than bone marrow?
Is more tolerant of histo-incompatible blood than donor cell.Wide availability of cord blood.
What are the risk of insertional mutagenesis?
Cancer, oncogene activation, inactivation of tumor suppressor etc.
What is the role of retrovirus in DNA transfer?
target cell must undergo division for integration to occur
What is the role of adenoviruses?
infect a wide variety of dividing and nondividing cells
What is the role of adeno-associated viruses?
Widespread in humnas so no adverse immune effects. Use to TX Hemophilliacs B patients
For what is Nuchal Translucency Test use for?
To test for All 3 types of Trisomies (13,18&21)
High levels of Inhibin A indicate what?
Down Syndrome
What do high and low levels of AFP indicate?
High levels indicate NTDs and Low levels indicate + All 3 trisomies
What do high and low levels of Free Beta HCG indicate?
High levels indicate Down Syndrome and low levels indicate trisomies 13 and 18
What do low levels of PAPP-A indicate?
+ for all 3 trisomies
What do low levels of UE3 indicate?
+ for all 3 trisomies
At what time is Amniocentesis performed?
15-16 weeks
What type of testing can be drawn from Amniocentesis fluid extract?
Karyotyping, DNA testing & AFP from fetal urine
What is the risk of miscarriage from performing an Amniocentesis?
1%
At what time is Chorionic Villus Sampling performed?
10-12 weeks
How is Chorionic Villus Sampling performed?
Transcervical or Transabdominal needle
What is the fluid type obtained in a Chorionic Villus Sampling?
Fetal trophoblastic cells
What is the risk of miscarriage from performing a Chorionic Villus Sampling?
1%
What is the risk of miscarriage from performing a Maternal Serum Screening?
No risk to fetus
When is Maternal Serum collected for screening?
16 weeks
What does Maternal Serum test for?
Down Syndrom and NTD
What are the risk associated with Ultrasounds and fetal echo?
No risk to either the baby or the mother.
At what time is sex of fetus usually able to be determine with and ultrasound?
15 weeks
What type of prenatal testing are recommended in the first trimester?
Nuchal Translucency, PAPP-A & Free Beta-HCG
What type of prenatal testing are recommended in the second trimester?
Ue3, AFP and Free Beta-HCG
What are the major cause of NTD?
Folic Acid deficiency
What are the 2 chromosomes related to Burkett’s Lymphoma?
Chromosome 8 & 14 translocation
What is characteristica about Burkett’s Lymphoma & what population is more susceptible?
Ch[8:14]= activated pro to-oncogene = Tumour in the jaw. Seen in Equatorial Africa.
Describe a bening mass
slow growing, no invasive.
Describe a malignant mass
fast growing invades proximal & distal tissues.
Describe Sarcoma
Mesenchymal origin i.e. bone, ct, muscle, nervous system.
Describe Carcinomas
Epithelial origin i.e. cell lining intestine, bronchi, mammary ducts.
Describe hematopoetic & Lymphoid
bone marrow & lymph nodes.
What is require to deactivate a tumor suppressor gene?
a 2 hit mechanism.
What is special about a Proto-oncogene?
It only requires a single mutation to go from normal to malignant.
What are the 2 chromosome involve in CML?
Chromosome 22 & 9 (Philadelphia Chromosomes)
What is commonly use to TX CML?
Imatinib(Gleevac) tx on tyrosine residue blocks ATP signals.
Is MEN-2 AD or AR?
AD
MEN-2 represents a mutation in what gene?
RET Gene for receptor tyrosine kinase
Does MEN-2 representa a LOF or GOF mutation?
GOF Mutation
With what type of tissue and/or organs is MEN-2 associated?
Medullary carcinoma of the thyroid and Phenochromocytomas of adrenal medulla —–> Over secretion of NE and Epi —-> Increase in HR, BP etc…
What is Retinoblastoma?
Mutation of Rb on Chr. 13
What is the normal function of Rb?
Normal function of Rb is to regulate G1/S phase; its normally not phosphorylated so it binds E2F and PREVENTS transcription.
What are the 2 possible types of mutation in Rb?
In inherited retinoblastoma (dominant trait), there are multiple bilateral tumors, having an early age of onset—one Rb1 mutation isinherited, and any mutation in the second allele would leadto cancer.orIn sporadic retinoblastoma, there are single unilateral tumors, having a late age of onset—two “hits” of the Rb1 mutation need to take place.
What are the 2 types of tumor suppressor genes?
-Gatekeeper = regulate proto-oncogene function. **Regulate various cell cycle points. Also regulate apoptosis.-Caretakers = Act more indirectly by maintaining genome integrity. **Correct mutations during DNA replication & Cell division.
Is Li-Fraumeni AR or AD mutation?
AD
What is mutated in Li-Fraumeni Syndrome?
Ch 17 –> TP53 a transcription factor that induces the synthesis of P21 use in cell cycle arrest.
How is TP53 active?
when phosphorylated
What is the function of Mdm2?
it inhibits TP53 by keeping it in the cytoplasm, so it doesn’t activate P21.
With what type of cancer is BRCA1 associated with?
BRCA1 on Ch 17 is associated with Breast and Ovarian cancer. Through the ATM cell cycle arrest pathway.
With what type of cancer is BRCA2 associated with?
BRCA2 on Ch 13 is associated with Breast cancer, gallbladder, pancreatic, male breast cancer.
Are BRCA 1 & 2 oncogenes or tumor suppressor?
Tumor suppressors
What are the type of inheritance? Mutation? Chromosome? associated with Familial Adenomatuous Polyposis (FAP)?
ADMutation in APCgeneChromosome 5
What is the function of APC?
The normal function = gatekeeper (binding beta catenin to phosphorylateand degrade; stops its oncogene activity) mutated APC = uncontrolledbeta catenin activity and c-myc transcription
What is FAP?
Develop colon cancer by age 40. It starts with THOUSANDS of benign polyps in large intestine =predisposition for cancer.
What is HNPCC?
Hereditary Non Polyposis Colon Cancer - Colon-rectal Cancer
What is the mode of inheritance in HNPCC?
AD
What is the defect in HNPCC?
Defect in DNA MisMatch Repair of normal tumor suppressor genes:MLH1MSH2MSH6Microsatellite Instability: from RER+ phenotype
What is Xeroderma Pigmentosa?
AR mutation. Ineffective nucleotide excision repair, UV light produce thymine dimers can’t be fixed.
What is Bloom Syndrome?
chromosomes instability
What are some of the possible clinical manifestations of Xeroderma Pigmentosa?
Skin cancer, cataract, neurological abnormalities etc…
What are some of the possible clinical manifestations of Bloom Syndrome?
growth deficiency, immune deficiency and increased cancer.
What is Ataxia telangiectasia?
AR chromosome instability. Causes Cerebellar ataxia and telangiectases
What is Fanconi Anemia?
Mutation in 8 different loci; chromosomes instability. Can cause Anemia and Leukemia.
What does Fanconi, Ataxia Telangiectasia, Bloom and Xeroderma have in common?
They are all Caretaker genes.
Whats and example of an inherited oncogene that may cause cancer?
RET gene —-> MEN-2
