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Genetics exam

Genetics block 4 exam

TermDefinition
Therapeutic cloning use of embryonic stem cells to form differentiated cell types of the body in culture
Reproductive cloning implantation of the embryo obtained by nuclear transplantation into the uterus of a woman to develop into a fetus
Hematopoietic Stem cells these cells can reconstitute the blood system after bone marrow transplantation
hydroxyl group [hydroxylation] phase I of drug metabolism = add a________ to the molecule, allow a side group to be more readily attached
CYP3A4 [highest %] CYP1,CYP2,CYP3 metabolize 90% of drugs but one CYP metabolizes the highest %
CYP2D6/CYP2C19 these two CYP variants are the slow metabolizing phenotypes
Phase 2 glucoronidation, acetylation, methylation are examples of what phase of drug metabolism
N-acetyltransferase [NAT2 ] Patients receiving Isoniazid therapy for tuberculosis Slow and rapid inactivation phenotypes – due to allelic variation in_________ gene,
thiopurine methyltransferase, TPMT 6-mercaptopurine and 6-thioguanine – treatment of childhood leukemia.These drugs are detoxified by______ encoded by____ gene
butyrylcholinesterase, BCHE Succinylcholine – normally hydrolyzed by ______enzyme which is encoded by 2 codominant alleles of_____ gene
Glucose-6-Phosphate Dehydrogenase Deficiency most common disease-producing enzyme defect of humans
primaquine, NADPH The antimalarial drug,________ was found to induce hemolysis in these patients with G6PD deficiency.deplete the cell of ______ and subsequently reduced glutathione - resulting in oxidative damage of RBC plasma membranes causes hemolysis.
anesthesia:all commonly used inhalational anesthetics (e.g., halothane) Malignant hyperthermia is an AD condition, more common in children and young adults.Can lead to dramatic adverse reaction to __________
Warfarin drug that is an anticoagulant used for prevention of thromboembolism. Acts by blocking the vitamin K epoxide reductase complex I (encoded by VKORC1) –reduces recycling of vitamin K
20% less Heterozygotes can handle_____% more or less warfarin?
Phase 1 Warfarin: undergoes phase ___ detox by CYP2C9
Patient Autonomy This principle justifies both informed consent and confidentiality
Justice Benefits and harms should be fairly distributed in society
[1]The reasons for a procedure.[2]The relevant benefits and risks of a procedure. [3]Alternative procedures along with their relevant benefits and risks in genetic testing patients must be informed about [3 things]?
benefits, risks Patients must understand these novel ______ and_____ before they can give informed consent to a test
“Nocebo” effect when a patient’s condition worsens more rapidly because of their knowledge that they have a disease
Roe v. Wade Current U.S. law is governed by the U.S. Supreme Court 1972_____V._______ decision which mandates that abortion must be legal through the first two trimesters
predisposition, carriage So it is better to postpone_______ and _______ testing until the child is an adult
(1) is necessary to prevent or lessen a serious and imminent threat to the health or safety of the patient or others and (2) is to a person(s) reasonably able to prevent or lessen the threat.” HIPPAA allows for a breach of confidentiality to prevent harm if a physician, “has a good faith belief that the disclosure: [2 things]
Tarasoff v. Regents of the University of California This court case ruled that:Doctors have a duty to warn people who are at risk of harm, and this includes not only the risk of violence, but also risk such as serious infectious diseases. He told his psychologist that he was planning to kill _____
The American Medical Association [AMA] This association______ suggests that physicians should tell patients that they expect the patient to inform their genetic family members who are subject to a preventable risk So the _____suggests that physicians should maintain confidentiality
Pate v. Threlkel Florida Supreme Court - 1995 this case ruled that confidentiality should be maintained because having the patient inform their family was a reasonable way to ensure that family members were informed of their risks
Safer v. Estate of Pack New Jersey Supreme Court - 1996 this case ruled that a now deceased doctor should have personally informed _____, and that the duty to warn justified a breach of confidentiality for avertable risk from genetic causes to genetic family members.
Molloy v. Meier Minnesota Supreme Court - 2004 court case ______ V._______ ruled that the duty to warn also included a patient’s genetic parents
cDNA In 2013, the U.S. Supreme Court ruled that only_____ can be patented
Genetic Enhancement is modification of a person’s genes that expands the person’s functioning above a normal or baseline level.might lead to increased social inequality, likely only affordable by the wealthy, and would give the wealthy a further competitive advantage
ice fish (Channichthyidae) the only vertebrates to lack hemoglobin
4 mol O2 per mol Hb Hemoglobin binds up to ____mol O2 per mol Hb
Microcytic/Hypochromic Iron deficiency,Lead poisoning, and THALASSEMIAS are categorized under what type of anemia?
Normocytic/Normochromic Acute blood loss, Bone marrow failure, Hemolytic anemias, SICKLE CELL anemia, Hb C and Hb D diseases are categorized under what type of anemia?
Macrocytic Megaloblastic,Non-megaloblastic are categorized under what type of anemia?
Cyanosis blue color of skin/mucus membranes due to low oxygenation of blood
Polycythemia increase in packed cell volume (hematocrit)
two α – like and four β – like In hemoglobin structure There are__#__α – like and __#__ β – like globins each coded by individual genes
Hb Barts (γ4) Hemoglobin represented by (γ4) is incapable of releasing oxygen under normal conditions
HbH (β4) Hemoglobin represented by (β4) is incapable of releasing oxygen under normal conditions
3 chromosome 16 There are ___#___clusters of α-like genes on chromosome ___
5 chromosome 11 There are ___#___clusters of β-like genes on chromosome ___
yolk sac, liver, spleen, bone marrow Embryonic globin synthesis occurs in the ______ between weeks 3 – 8, but at week 5, globin synthesis begins to switch to the _____ ,the synthesis is switched to the ____ and then to the ______
HbF is the predominant Hb in neonates and is about 70% at birth, in adulthood, it is only 1%
β-globin gene Locus Control Region (LCR) Deletion of _______ leads to εγδβ-thalassemia –failure to express the genes of the β-globin cluster on one chromosome
active chromatin hub (ACH β-globin gene Locus Control Region (LCR) Together with DNA-binding proteins = _______
β-globin gene Locus Control Region (LCR) Contains 5 DNAase 1-hypersensitive sites (HSs)– to maintain open chromatin configuration of the locus – for transcription of β-globin complex
Functions of Locus Control Region (LCR) generation of a highly accessible LCR holocomplex; recruitment of transcription & chromatin-modifying complexes to the LCR;establishment of chromatin domains permissive for transcription; transfer of transcription complexes to globin gene promoters.
Locus Control Region (LCR) Patients with deletions of______ express no genes (< 1%) of β-cluster –i.e. they present with εγδβ-thalassemia
globin switching Knowledge of the mechanisms of _______ _______ may make it possible to up-regulate the expression of the γ-chain – providing a potentially effective treatment of β-thalassemia
α-globin gene, α-chains mutations in the ___globin gene. Affects 25% of the ___chains.Can cause severe disease during fetal development as well as in postnatal life
β-globin gene, β-chains Mutations in the ___globin gene. Affects 50% of the ___chains No prenatal consequences
non-thalassemia hemoglobinopathy Missense mutations in coding sequence which make protein unstable and reduce its abundance - a _________hemoglobinopathy if it causes the tetramer to be unstable
β-thalassemia this hemoglobinopathy is due to an Introduction of a premature stop codon by either nonsense or frame-shift mutation -
Hb Kempsey this hemoglobinopathy is due to a missense mutation in a subunit interface that locks Hb into high O2-affinity state, reducing delivery to tissues. shift O2 saturation curve to the left
Hereditary Persistence of Fetal Hemoglobin this hemoglobinopathy is due to Mutations in some Hb regulatory elements lead to continued production of γ-globin in adults. there is an Impaired switch from γ-globin to β-globin synthesis. the deletion brings enhancers closer to γ-genes
Thalassemias subcategory of hemoglobinopathy due to Decreased synthesis of either α or β globin chains
unstable However, sickle cell disease and HbC disease do not have _____tetramers
(HbS) Sickle cell this hemoglobinopathy has the ability to polymerize into rigid fibers. Due to single nucleotide substitution –change 6th amino acid of the β-globin from glutamic acid to valine: Glu6Val. the valine side-chain fits into the hydrophobic pocket,
(HbC) this hemoglobinopathy has ability to form crystals. Glu6Lys An acidic amino acid is replaced by a basic amino acid(negative electric charge decreased 4 units).
HbS and HbC The mutations causing Hb__and Hb__ are at the same position in the β-globin gene
African-American military recruits Sickle cell trait – heterozygosity has been linked with sudden death in __________ during vigorous exercise:
low O2 tension Sickle cell anemia – homozygosity .Tendency for red cells to sickle under conditions of _______
sodium Metabisulfite Sickle cell Test: venous blood mixed with 2%_____ _______ and placed on microscope slide with cover
Sickle cell – HbS β-chain - Glu6Val. An acidic amino acid is replaced by an uncharged hydrophobic amino acid (negative electric charge decreased 2 units)
malaria due to P. falciparum The high prevalence of the sickle cell gene in sub-Saharan Africa and southern Asia is due to its protective effect against
(HbC) this hemoglobinopathy Causes a mild hemolytic disorder (red cells as target cells (codocytes)
Hb Hammersmith this hemoglobinopathy is due to a point mutation causes an amino acid substitution in β-chain: Phe42Ser .unstable and has low affinity for O2 causing cyanosis
Hb Gun Hill this hemoglobinopathy is due to a Deletion of 15 bp (Codons 91 – 95) in the β-chain . tetramer is unstable leading to hemolysis
Hb Philly this hemoglobinopathy is due to point mutation causing β Tyr35Phe Prevents formation of a H-bond between the Tyr and α Asp 126 at the α1:β1 interface. Unstable Hb Chronic hemolytic anemia
the T or tense (taut) Normal Hb A exists in two stable states one is – the ___________ low affinity form
the R or relaxed Normal Hb A exists in two stable states one is –the _______ high affinity form
decreased affinity for O2 A shift to the right on the O2 Saturation/tension curve indicates________
Hb Kansas - this hemoglobinopathy is due to a point mutation in β Asn102Thr locks Hb into low affinity form - cyanosis
Hb Hyde Park this hemoglobinopathy is due to a single nucleotide substitution leads to βHis92Tyr. makes oxidized heme iron resistant to methemoglobin reductase. methemoglobin persists, but cannot bind oxygen. cyanosis
HB Tak this hemoglobinopathy is due to a frameshift mutation near the end of the β-chain allowing read through to a new downstream stop codon .prevents formation of a stable deoxy structure and greatly increases affinity (Inheritance is AR)
Hb E this hemoglobinopathy is due to : an exon mutation creates a cryptic donor site– most common structurally abnormal Hb – In SE Asia 1 million homozygotes and 30 million heterozygotes
a-Thalassemias Is the absence of a-chains, b-like chains form tetramers: Hb Bart’s (g4) and Hb H (b4). occurs in utero
Hb Constant Spring this hemoglobinopathy is due to a substitution in stop codon UAA or UAG to CAA or CAG leads to read-through to next stop codon –adds 31 amino acids to a-chain
b-Thalassemias Decreased b-globin synthesis leads to hypochromic microcytic anemia.Imbalance in globin synthesis leads to precipitation of a-chains and red cell damage.α globin precipitates in red cells and forms Heinz bodies. Does not occur in utero
bite b-Thalassemia: Multiple Heinz bodies can be seen in target cell RBCs and can turn into _____cells or degmacytes due to ROS
thalassemia major Most persons with two affected b - alleles have_________ .
Thalassemia Minor Carriers of a single b-thalassemia allele have ______ and are generally Clinically well
b0–thalassemia - Mediterranean this hemoglobinopathy is due to mRNAs cannot direct synthesis of b-globin because the mutation generates a premature stop codon – 2 mutations near the amino-terminus illustrate this:Nonsense mutation converts codon 39 CAG to UAG Gln to STOP
Complex Thalassemias Large Deletions cause these hemoglobinopathies
inborn errors of metabolism Garod’s historical work, which led to the concept of _____________caused by missing or false steps in the body’s chemical pathways.
ochronosis Deposition of homogentisic acid-derived alkapton in cartilage and collagenous tissues which account for blue – black pigmentation of mainly the palate, ears and in the sclera of the eyes
Alkaptonuria a rare autosomal recessive disease .Caused by a deficiency of the enzyme homogentisic acid oxidase. Characterized by urine that turns black on standing. Also deposited in cartilage (ochronosis), heart valves and intervertebral discs
phenylalanine and tyrosine Homogentisic acid is an intermediate in the catabolism of the amino acids, _________and __________
Nitisinone (Orfadin) Originally developed as a herbicide - reversibile inhibitor of 4-hydroxyphenyl pyruvate dioxygenase. Being tried in alkaptonuria to see if it can prevent ochronosis in older patients
alkaptonuria In 1977, an ochronotic Egyptian mummy was described – thought to be due to __________
Housekeeping proteins these type of proteins are present in every cell, role in maintenance of cell structure and function,encoded by ~90% of the mRNA. example:DNA polymerases
Speciality proteins these proteins are produced in only one or a limited number of cell types, function characteristic for the cells where are expressed, encoded by ~10% of the mRNA, example: phenylalanine hydroxylase in the liver
Enzymopathies this category of disorders result in disease due to either substrate accumulation and/or product deficiency or by accumulation of abnormal metabolites
phenylketonuria [PKU] refers to the presence of phenylketones (phenylpyruvate) in urine, which occurs when blood and tissue levels of Phe are high)
phenylalanine hydroxylase (PAH), or tetrahydrobiopterin (BH4) PKU is Caused by: i] deficiency of the enzyme _______________ ii] deficiency in the synthesis or recycling of the cofactor, __________
phenylketonuria [PKU] This disorder leads to mental retardation,Seizures, albinism (excessively fair hair and skin) and a "musty odor" to the baby's breath,sweat and urine (due to phenylactate one of the phenyl compounds produced.
heel prick test A droplet of blood from the _______, dried on filter paper – analyzed for blood phenylalanine levels and for phenylalanine-tyrosine ratio. to screen for PKU
Dietary modifications this type of treatment aims to prevent phenylalanine accumulation, but still allow enough for normal development
phenyalanine Turkey and tuna are foods high in ___________
compound heterozygotes Most PKU patients are_______ _______ i.e. they have two different disease-causing alleles
Tetrahydrobiopterin[BH4] Metabolism Patients recognized by failure to improve after low-phenylalanine diet – still develop severe neurological problems because they have Defects in _______________
tyrosine hydroxylase tryptophan hydroxylase BH4 is a cofactor for 2 other enzymes________&________ involved in synthesis of neurotransmitters (DOPA, norepinephrine and serotonin):
oral BH4 treat variant PKU with ____ ______ – to reduce plasma phenylalanine levels
glycosylation the example of Mendelian susceptibility to Mycobacterial disease (MSMD) Describe diseases due to gains in _______
Lysosomes enzymatically degrade macromolecules such as glycosaminoglycans (proteoglycans), glycoproteins, glycosphingolipids, sphingomyelin, glycogen as well as larger structures, such as damaged cellular organelles and micro-organisms after phagocytosis
acid hydrolases Lysosomal enzymes , most are______ ______ , but not all
Pompe disease lysosomal glycogen accumulates at the cell periphery
chaperones Pharmacological __________ can improve targeting to lysosomes
Tay-Sachs disease Results from deficiency of hexosaminidase A and the inability to cleave the terminal N-acetylgalactosamine from GM2 to produce GM3. “cherry red spot”.adult patients develop a schizophrenia-like psychosis
Sandoff disease Mutations in the HEXB gene leads also to a deficiency of hexosaminidase A and B resulting in this disease.there is an inability to convert GM2 to GM3 and also to remove the terminal N-acetylgalactosamine from the globoside
Infantile Tay-Sachs “cherry-red spot” in the retina. Progressive neurological deterioration continues - death occurs between 2 to 4 years of age. Deafness, blindness, inability to swallow, atrophy and paralysis.
sialidase treatment for Tay-Sachs disease substrate reduction therapy – using ________ to bypass the hexosaminidase A step in degradation;
pyrimethamine treatment for Tay-Sachs disease .increasing residual hexosaminidase A activity with this drug _______
Tay-Sachs disease Ashkenazi Jews, Cajuns, and French Canadians 100 X higher incidence of ________ disease than in other populations. Due to founder effect or heterozygote advantage
metachromatic leukodystrophy this disease is caused by sulfatidase deficiency
Hyaluronic acid ______ is non-sulfated and binds proteoglycan momomers via a linkage protein to form proteoglycan aggregates
glycosaminoglycans Deficiency of any one enzyme leads to accumulation of its substrate and development of pathology – the mucopolysaccharidoses –__________ appear in urine and are important aids to diagnosis
Hurler disease deficiency of α-L -iduronidase - heparan and dermatan sulfates accumulate.Course facies,low nasal bridge,open mouth ,upper airway obstruction,Corneal clouding,dwarfing,Mental retardation,Death before age 10
Scheie syndrome Autosomal recessive deficiency of α-L-iduronidase, Corneal clouding,Valvular heart disease,Normal intelligence, Late-onset form at 5 – 15 rears of age
allelic heterogeneity Hurler and Scheie disease illustrates ________ heterogeneity
Hunter syndrome (MPS II) An X-linked recessive disorder, Deficiency of iduronate sulfatase,Blocks degradation of heparan and dermatan sulfates,No corneal clouding, Macrocephaly, hepatosplenomegaly, Mild to severe mental retardation
Sanfilippo syndrome (MPS III) this disease has Four different enzyme deficiencies on the pathway of heparan sulfate degradation result in phenotypically similar disorders.Severe nervous disorders and retardation
locus heterogeneity Sanfilippo syndrome (MPS III) illustrates the principle of_____ heterogeneity
Hurler Aldurazyme is the drug treatment for ______ disease.Does not treat the underlying disease, just the symptoms
Hunter Elaprase is the drug treatment for ______ disease
UDP-NAcGlc phosphotransferase, I-Cell disease: deficiency of ____________
mannoses I-Cell disease: lack UDP-NAcGlc phosphotransferase, no_______ get phosphorylated.
inclusion bodies I-cell disease: all lysosomal enzymes, instead of being targeted to the lysomes, are secreted from the cells, they will accumulate all sorts of macromolecules in the form of ________ _______
4 The gene GNTPA is found on chromosome ___#___ It encodes the enzyme UDP-NAcGlc phosphotransferase
I-cell disease mental retardation, skeletal deformities, coarse facial features, gingival hypertrophy, growth retardation, hearing loss, noisy breathing and death by age 5-8 years.
Mendelian susceptibility to Mycobacterial disease (MSMD) missense mutations in the gene for interferon-y-receptor 2 (IFNGR2) – generation of novel N-glycosylation sites in the mutant IFNGR2 protein. Produces an overly glycosylated receptor that fails to respond to interferon-y
Homocystinuria dislocation of the lens, mental retardation, osteoporosis, long limbs and knock knees, thromboembolism of both veins and arteries,accumulation of homocysteine, megaloblastic anemia developmental delays, failure to thrive
Non-classical homocysteinuria Defects in methylene-H4-folate reductase – impairs the function of methionine synthase
pyridoxine (vitamin B6) Homocystinuria – treatment: Administration of large amounts of_________
Homocystinuria betaine and low methionine diet are treatments for what disease?
vitamin B12 vegans can develop acquired vitamin_______ deficiency – abnormalities similar to those found in the homocystinuria caused by mutations in several genes
α1-Antitrypsin (α1AT ) Deficiency Autosomal recessive disorder,Risk of chronic obstructive lung disease (emphysema) and cirrhosis of the liver
α1AT protein a protein that is a serine protease inhibitor or serpin – inhibits elastase released from neutrophils in the lower respiratory tract.Defect can be on hinge region or beta pleated sheet region
chromosome 14 α1-AT gene (SERPINA1) is located on chromosome__#__
conformational The Z form of α1AT deficiency mimics what is seen in sickle cell disease – both are examples of ________ diseases. Mutations causes a change of shape or size of a protein - leading to self-association and tissue deposition.
Z allele α1AT ____allele – novel property of the mutant protein – tendency to aggregate, trapping it within the rough endoplasmic reticulum of hepatocytes
20% α1AT with the Z mutation has only ____% ability to inhibit neutrophil elastase
Acute Intermittent Porphyria this disease has a deficiency of porphobilinogen deaminase –PBG deaminase (enzyme in the biosynthetic pathway of heme).ALA and porphobilinogen accumulate in the urine. Urine darkens. patients are not photosensitive
transport CFTR gene as an example of a gene linked to a _______ defect (cystic fibrosis)
receptor Familial hypercholesterolemia – an example of a _______ defect
structural protein Duchenne and Becker muscular dystrophies – examples of a ________defect
LDL receptor _______ receptor = polypeptide affected in the most common form of familial hypercholesterolemia
Familial hypercholesterolemia disease - High levels of plasma cholesterol (LDL-cholesterol)Elevated risk of atheroma and myocardial infarction
atheroma deposits of LDL- cholesterol in the coronary arteries
xanthomata cholesterol deposits in skin and tendons
xanthelasma cholesterol deposits in eye lids
corneal arcus deposits of cholesterol on the periphery of cornea
Familial hypercholesterolemia Both heterozygotes and homozygotes of ___________disease –develop premature heart disease with; atheroma, xanthomata, xanthelasma , corneal arcus
clathrin LDL receptors are located in coated pits lined by _____
LDL apheresis , liver transplants these two treatments __________and _______ offer the best hope for homozygous Familial hypercholesterolemia patients
CFTR gene ________ gene encodes a protein = chloride channel located in the apical membrane of the epithelial cells affected in the lungs, liver, pancreas, digestive tract, reproductive tract and skin
Cystic fibrosis Pulmonary disease,Pancreatic disease, Postnatal lower intestinal tract obstruction (Meconium ileus ), congenital bilateral absence of the vas deferens , death before age 33 in half of the patients
chromosome 7q31 CFTR gene Located on chromosome _____, covers 190kb of DNA
∆F508 deletion of ________ is the most common allele in whites that have Cystic Fibrosis ~70%
Non classical Cystic Fibrosis Mutations in the epithelial sodium channel gene SCNN1 causes_______
∆F508 allele American College of Medical Genetics recommend screening for the _____allele and 22 other mutations
Duchenne Muscular Dystrophy (DMD) X-linked disorder caused by mutations in Dystrophin gene. develop muscle weakness at age 3 to 5-difficulty climbing stairs and rising from sitting position (Gower sign),children confined to wheelchair by age 12
creatine kinase patients that have Duchenne Muscular Dystrophy (DMD) have an increased (50-100 times) level of _______ ______
Becker Muscular Dystrophy (BMD) X-linked disorder caused by mutations in dystrophin gene – still express some dystrophin, milder phenotype, still walking at 16 years
Dystrophin Protein that anchors a large protein complex at the cell membrane. Essential for the maintenance of muscle membrane integrity – links the extracellular matrix to the actin cytoskeleton
germline mosaicism 80% of boys born with Duchenne – have no family history of disease – may be due to maternal ________ ________
introgression One of the 12 major dys44 haplotypes named B006, appears to be an _________ from a Neanderthal-modern human pairing and is not found in sub-Saharan Africans
Osteogenesis Imperfecta (OI) Due to mutations in collagen structural genes,Predispose to easy fracturing of bones, skeletal deformities.
Glycine-X-Y Collagen type I:Triple helical collagen – 338 tandemly arranged ___-____-___repeats:
decrease , production Mutations that_____ the _____ of type I collagen cause (mild phenotype) Type I OI
alter , structure Mutations that _____the_____ of type I collagen cause Types II (perinatally lethal), III and IV OI
Osteogenesis Imperfecta type I Collagen normal but Quantity reduced.the cells produce about half the normal amount of type I collagen.Premature termination codons in one COL1A1 allele Loss of half of the mRNA – production of half of normal quantity of type I procollagen molecules
carboxy Most type II mutations towards ________ terminus or in the middle. Replacement of glycine with aspartate (acidic),very disruptive – interfere with the propagation of the collagen helix
germline mosaicism receiving Osteogenesis Imperfecta from an unaffected parent is called ______ _______
the bisphosphonates new class of drug ________ reduce bone resorption have been shown to increase bone density and bone mineral content in patients with severe Osteogenesis Imperfecta[OI ]– reduce fracture rates in children with OI
Ehlers-Danlos syndrome skin fragility, hyperextendibility, easily damaged blood vessels, joint hyperplasia,2 types, due to mutations affecting the structural genes for collagen I and III chains
lysyl oxidase Ehlers-Danlos syndrome type IV the defect is in post-translational processing of collagens I and III due to a deficiency of __________ collagen is unstable as poorly cross-linked
Alzheimer Disease (AD) Manifests in the sixth to ninth decade of life, exceptions as early as third decade.Degeneration of neurons from the cerebral cortex and hippocampus. progressive deterioration of memory and higher cognitive functions-behavioral changes
β-amyloid precursor protein(βAPP) mutations in genes encoding__________protein, pre-senilin 1, pre-senilin 2 – autosomal dominant Alzheimer Disease (AD) inheritance
APOE gene mutations in ______gene – no association with monogenic Alzheimer Disease (AD) – increase in susceptibility to non-familial Alzheimer Disease (AD)
β-amyloid peptide -Aβ; tau protein Deposits of 2 fibrillary proteins______&______ in the brain are the most important pathological abnormalities in Alzheimer Disease [AD]
Aβ peptide peptide generated from the βAPP (chromosome 21),found in the amyloid/senile plaques in the extracellular space of the brain. cleaved by different proteases (secretases)
Tau protein microtubule-associated protein expressed in neurons – promotes the assembly and stability of microtubules – found in plaques
lipid rafts Alzheimer Disease (AD) Abnormal cleavage in βAPP in ____ ____ by different proteases (secretases)
Amyloid Precursor Protein (βAPP) 90% cleaved by α-secretase - form the_____ peptide
Aβ-40 , Aβ-42 Amyloid Precursor Protein (βAPP) 10% cleaved by β and y-secretase - form the ____ and _____ peptides
Aβ-42, Aβ-40 Alzheimer Disease (AD) _____peptide –more neurotoxic – more fibrillogenic than____ peptide
Aβ42 Mutations in βAPP, presenilin 1 and presenilin 2 – increase production and accumulation of ______ peptide
E4 allele Alzheimer susceptibility gene _____ allele of APOE gene –over expressed in AD patients, associated with early onset AD development
protective E2 allele –of APOE gene has a __________ effect
mtDNA Rate of mutations for ______ is 10 times higher than the rate of nuclear DNA
mitochondrial myopathies disorders characterized by– ragged red fibers, Inherited maternally, encephalopathy,proliferation of abnormal mitochondria in degenerating muscle fibers, ataxia, retinal degeneration, loss of function of the external ocular muscles
OXPHOS Production of energy for the cell as ATP,Production of reactive oxygen species,Integration of signals that initiate apoptosis are Functions of _______
Homoplasy having a pure population of normal or mutant mtDNA
Heteroplasmy having a mixed population of normal and mutated mtDNA. means that mt diseases show reduced penetrance, variable expression and pleiotropy
mitochondrial genetic bottleneck Number of mtDNA molecules within each oocyte is reduced before being amplified to the total number in the mature oocytes =________ ________ ________
Parkinson disease Somatic mtDNA deletions – common in dopaminergic neurons of the substantia nigra in aging individuals and individuals with _______
phenotypic threshold There is a ______ ______ effect associated with mtDNA heteroplasmy
deletions, other mutations 60% threshold for disorders due to _____ in the mtDNA. 90% threshold for disorders due to _____ ______
MELAS (mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes) specific mutant mtDNA: A3243G substitution in the tRNA leu(UUR) gene most commonly associated with ______.diabetes and deafness, chronic progressive external ophthalmoplegia, cardiomyopathy, myopathy
mt DNA Both nuclear and ______contribute polypeptides for OXPHOS
Leber's Hereditary Optic Neuropathy [LHON] disorder: mutations generally homoplasmic, rapid loss of central vision, optic nerve atrophy in young adult, increased penetrance in males
Anticipation Myotonic dystrophy is an Example of ________.
Fragile X syndrome X-linked syndrome, CGG repeat in the 5’UTR of the FMR1 gene. Loss of FMRP protein function – mental retardation, learning deficits, macro-orchidism, connective tissue dysplasia
Friedreich Ataxia Expansion of GAA repeat in the FRDA gene (frataxin) Most common inherited spinocerebellar ataxia.Usually occurs before adolescence – incoordination of limb movements, speech problems, absent tendon reflexes, scoliosis, deformed feet
frataxin Loss of function of_______ = increased levels of mitochondrial iron, impaired heme synthesis, reduced activity of Fe-S containing proteins (e.g. complexes I and II of the mitochondrial respiratory transport chain
3’UTR Myotonic Dystropy type1 -Autosomal dominant disease .Expansion of CTG repeat in the_______ of the DMPK (protein kinase) gene . manifestation: muscle weakness, wasting, cardiac conduction, testicular atrophy, insulin resistance, cataract
intron 1 Myotonic Dystropy type2 -Autosomal dominant disease Expansion of CTG repeat in the ____ of the gene encoding zinc finger protein 9
Huntington Disease (HD) Autosomal dominant neurodegenerative disorder Expansion of more than 40 repeats of the codon CAG in the coding region.Manifestations: neurodegeneration, athetosis, loss of cognition, psychiatric abnormalities
insoluble aggregates Hallmark of Huntington disease:______ ______ of the mutant protein and other polypeptides in the nuclear inclusions (as a result of the cellular responses to misfolding of huntingtin)
danazol example of modulation of gene expression using ______ in hereditary angioedema . increases the mRNA for the C1 inhibitor – frequency of the attacks reduced
decitabine [deoxycytidine analog] examples of modulation of gene expression using _______ in β-thalassemis/sickle cell disease. inhibits methylation, increase of γ-globin gene expression – increase in Hb F
complete removal of milk [is not an essential nutrient – it can be eliminated entirely -e.g. galactose] Classical galactosemia (inborn error of carbohydrate metabolism – deficiency of galactose-1-P uridyltransferase) can be treated by?______
thyroxine _________administration can prevent mental retardation in patients with congenital hypothyroidism
Sodium benzoate, phenyl butyrate Urea cycle disorders can be treated with _____ ______ or ________
non-absorbable resins, cholestyramine Familial hypercholesterolemia ; administration of______ like______ (bind bile acids in the intestine)diversion of an increased fraction of cholesterol to bile acid synthesis, more hepatic LDL receptors are produced= reduction in LDL cholesterol
statins Familial hypercholesterolemia in heterozygotes treatment: inhibitor ________ administrated (reduction of LDL cholesterol more than 60%)
curcumin Cystic Fibrosis treatment drug________shown to inhibit a calcium pump in the ER – impairs binding of the mutant by the chaperone - normalization of the chloride transport – increased survival
gentamicin Cystic Fibrosis treatment drug________, facilitates the translation to “skip over” a premature stop codon
plasma fractions hemophilia patients treated by infusion of ______ ______ enriched for factor VIII or IX – to prevent or arrest bleeding episodes
smoking α1AT deficiency treatment -avoidance of ______
α1AT α1AT deficiency treatment by delivering _______to the pulmonary epithelium and alveolar interstitial fluid
PEG-ADA: by attaching polyethylene glycol (PEG) Treatment for ADA deficiency: Administration of bovine _______
interferons PEGylated _________ α2a/2b used to treat hepatitis C infections
laxative (Macrogol) PEG has a good safety record as also used as a _______ and excipient
Gaucher Imiglucerase, Velaglucerase and Taliglucerase used to treat_______. terminal sugars are removed to expose the α-mannosyl residues –target to the macrophage – enzyme is internalized and delivered to the lysosome
Fabry (Fabrazyme) used to treat _______
Gaucher disease due to deficiency of glucocerebrosidase – accumulation of glucocerebroside in lysosomes of macrophages– enlargement of liver and spleen
RNA interference (RNAi) can be used to degrade a specific target RNA
Bone Marrow Stem Cells Transplantation ____________used to treat: lysosomal storage diseases (Hurler and Hunter syndromes)
Krabbe disease (globoid cell leukodystrophy) white matter degenerative disorder, deficiency of galactocerebrosidase
Bone Marrow Transplantation Krabbe disease treated with ______
familial hypercholesterolemia Liver transplantation as treatment in homozygous _______ _______
Cancer _____cells can self-perpetuate and produce progenitor cells treated by chemotherapy or radiation
Somatic stem _____ _____ cells: divide by asymmetric cell division, reside in "niches", not Pluripotent
asymmetric Somatic stem cells: divide by ________cell division, reside in "niches", not Pluripotent
Embryonic stem _____ _____ cells are pluripotent and divide using symmetrical cell division
symmetrical Embryonic stem cells are pluripotent and divide using______ cell division
leukemia SCID X1 trial activated LM02 gene- and caused _______ in patient
Ormosil- a nonviral vector- organically modified silica
adenoviruses viral vector ________infects both dividing/nondividing cells, inserts of 30-35kb, strong immune response-->death
adeno-associated viruses Major advantages of this viral vector _______include having no disease association in humans and limited innate immunity.
Ex vivo introduction of the gene into cells that have been cultured from the patient and reintroduced after transfer
In vivo injection of the gene into the tissue or extracellular fluid of interest
Retroviruses RNA viruses with few structural genes that can be removed and replaced with the gene of interest.are nontoxic to the cell, only a low number of copies of viral DNA integrate into the host, stable,up to 8kb of added DNA
X-linked Severe combined immunodeficiencies [SCID] leads to failure to thrive and death due to infections (lack functional T and B cells), mutation in the X-linked gene encoding the yc-cytokine receptor subunit of interleukin receptors
SCID-X1 trial trial that injected gamma c gene into Moloney murine leukemia virus – ex vivo infection CD34+ cells from patients
chromosome 19. AAV-2 -this virus always inserts its contents into the same place on chromosome ______
Stem cells ______ cells :self-renewing cells that have the ability to proliferate to form differentiated cells specific for each tissue type
pharmacokinetics rate at which the body absorbs, transports, metabolizes or excretes drugs or metabolites
pharmacodynamics response to the drug due to allelic variation in the drug’s downstream targets
Thalassemias this hemoglobinopathy category has the classic symptom described as "hair on end" bone expansion .
Created by: SabaMDJuan