Term
| What type of problems are associated with autosomal recessive mutations? |
|
Definition
Problems with:
Enzymes
Proteins involved in transport and storage |
|
|
Term
| What types of problems are associated with autosomal dominant mutations? |
|
Definition
Problems with:
Structural proteins
Proteins involved in growth, differentiation, and development
Receptor and signaling proteins. |
|
|
Term
| Protein defects degree of severity. |
|
Definition
Null mutation - Underlying mutation completely destroys a protein.
Loss of function - Mutation reduces protein' activity
Gain of function -Mutation alters the proteins activity or conveys new function |
|
|
Term
| Four mendelian modes of inheritance. |
|
Definition
Autosomal dominant
Autosomal recessive
X-linked dominant
X-linked recessive |
|
|
Term
| What form of inheritance does not follow Mendelian rules? |
|
Definition
| Mitochondrial inheritance |
|
|
Term
| Recessive vs Dominant Inheritance |
|
Definition
Recessive: One normal allele enough to prevent disease. Mostly observed in enzymes, proteins involved in transport or storage
Dominant: One defective allele is enough to cause disease. Mostly observed in structural proteins or proteins involved in growth, differentiation, development, signalling |
|
|
Term
| Causes of Dominant inheritance |
|
Definition
Haloinsufficiency: Not enough gene product being produced
Dominant negative effect: Abnormal protein interferes with function of normal protein
Gain of function mutation: Mutated protein has a new and inappropriate function
Lack of Backup (Two hit model): Predisposition inherited as a dominant trait. |
|
|
Term
|
Definition
Males have one X chromosome. females have two (one is inactive)
Fathers pass X chromosome to daughters, Y chromosome to sons
Y-chromosome initiates male development |
|
|
Term
| How do you tell male from female cells? |
|
Definition
| Barr bodies made up of inactivated X-chromosomes that condence at the periphery of the nucleus |
|
|
Term
| Mitochondrial inheritance |
|
Definition
| Does not follow mendelian rules. Mitochondria come from ovum and are inherited from the mother. Cells have many mitochondria with many copies of the chromosome. variable expression. |
|
|
Term
|
Definition
| When cells have different number of mutant mitochondria. |
|
|
Term
| Characteristics of an autosomal recessive pedigree. |
|
Definition
Affected children usually have normal parents
Both sexes are equally affected
Consanguinity increases the risk |
|
|
Term
|
Definition
Biochemistry: Defect in phenylalanine hydroxylase. Phenylalanine not converted to tyrosine and accumulates and damages the developing central nervous system
Genetics: Inborn Error of Metabolism. 1/2,900 Newborns. Heel prick soon after birth. Analysis of blood phenylalanine levels (Guthrie card blood spot. Caused by mutations in PHA (612349): 13 exons, spans 90kb. 15 common mutations. |
|
|
Term
| Cystic Fibrosis: Overview |
|
Definition
Biochemistry: Defect in chloride channel
Symptoms: pulmonary problems, pancreatic malfunction.
Genetics: Gene is 6.2 kb, 1388 AA residues, 27 exons over 188 kb. delta508 accounts for 70% of mutations |
|
|
Term
| Five classes of cystic fibrosis |
|
Definition
Class I: Defective protein production
Clas II: Defective protein maturation/processing (deltaF508 mutation)
Class III: Defective channel regulation/gating
Class IV: Altered channel conductance
Class V: Altered protein stability |
|
|
Term
| Cystic fibrosis: Genotype/Phenotype correlation |
|
Definition
Pancreatic insufficiency Two mutations from classes I, II, or III
Pancreatic sufficiency: Milder, Mutations from classes IV and/or V |
|
|
Term
| Cystic Fibrosis: Diagnosis and Therapy |
|
Definition
Diagnosis: Sweat chloride test. Patients have 2-5 times the amount of sodium chloride in sweat and can be done as early as 48 hours after delivery
Treatment: Chest percussion, antibiotics and bronchodilators, pancreatic enzyme replacement, lung transplant. Gene replacement therapies (largely unsuccessful) |
|
|
Term
| Examples of diseases caused by different modes of Dominant inheritance. |
|
Definition
Haploinsufficiency - Osteogenesis imperfecta type I
Dominant Negative effect - Osteogenesis Imperfecta type II
Gain of function mutation: Toxicity of protein in Huntington disease
Lack of backup: Retinoblastoma |
|
|
Term
|
Definition
Different mutation in the same gene cause different phenotypes
Mutations can be gain-of-function or loss-of-function
Cystic Fibrosis |
|
|
Term
|
Definition
Mutations in different genes cause the same phenotype
Leber Congenital Amaurosis |
|
|
Term
|
Definition
Individual genetic background modifies the phenotype
Cystic fibrosis |
|
|
Term
|
Definition
Mutation causes multiple phenotypes. Not all carriers of the same mutation display the same set of phenotypes
Neurofibromatosis |
|
|
Term
| Characteristics of an autosomal dominant pedigree |
|
Definition
Affected child has at least one affected parent
Both sexes equally affected
Disease can be transmitted from father to son
Often homozygotes are more severely affected than heterozygotes |
|
|
Term
|
Definition
Complete penetrance
Variable expressivity
Defect in Gene NF1: Neurofibromin. cytoplasmic, expressed in neurons, Schwann cells, oligodendrocytes, astrocytes and leukocytes.
No clear genotype/phenotype correlation established
Diagnosis: Two or more of Cafe aulait macules (at least 6, dm of 1.5 cm) Lisch nodules, 2 or more neurofibromas, 1 or more plexiform neurofibromas |
|
|
Term
|
Definition
Expression: variable and age dependent
Expressivity: Severity of symptoms |
|
|
Term
|
Definition
| The percentage of people with the disease gene who develop symptoms |
|
|
Term
|
Definition
Gain of function mutation in Huntington gene (IT15)
Trpilet expansion (strand slippage) in genes causes protein instability- higher the number of CAG repeats, the more severe the disease. 35-40 repeats pre-mutation.
DNA repeats bind to HPA-1 molecule |
|
|
Term
|
Definition
| Repeats and severity increase each generation- the size of the repeat can expand on transmission-gametogenesis |
|
|
Term
|
Definition
Defect in fibroblast growth receptor (FGFR3). New mutations, gain of function mutation, and dominant negative effect
Inhibition of bone growth leads to short stature, reduced fitness. |
|
|
Term
|
Definition
| Allele carrier of autosomal dominant disease has reduced chance of reproduction |
|
|
Term
|
Definition
| New mutations appear constantly and compensate for loss of mutant alleles |
|
|
Term
|
Definition
Dominant negative effect
Mutations in type I collagen causing predisposition to fracturing of bones, skeletal deformity. |
|
|
Term
| Allele heterogeneity in Osteogenesis imperfecta |
|
Definition
Different mutation in the same gene can result in different phenotypes
Severity depends on the mutation
Effects on protein function vary
Decrease in rate of helix formation
Change in rate of post-translational modification
Decrease in rate of secretion and degradtion
Defect in structure of collagen fibrils
Poor mineralization (in bone) |
|
|
Term
| Four Types of Osteogenesis Imperfecta |
|
Definition
Type I (mild): Null mutations in the procollagen alpha1(I) gene. Phenotypes are brittle bones and blue sclerae- but no bone deformities (haploinsufficiency)
Type II (perinatal lethal): Missense mutations abnormal protein and dominant negative effect.
Type III (progressive deforming): Missense mutations, abnormal protein.
Type IV: Mildest of OI types, missense mutations causing moderate bone deformities, dentinogenesis imperfecta and a predisposition to bone fractures. |
|
|
Term
|
Definition
Familial Hyerchleserolemia (FH). Haploinsufficiency
Defect in the LDL receptor, over 400 mutations identified.
Heterozygotes - Elevated LDL levels (2-fold) not enough receptors to clear LDL from serum
Homozygotes- Even more elevated LDL levels (4-fold) |
|
|
Term
| 5 Classes of LDL receptor mutations |
|
Definition
Class 1: Receptor Synthesis (ER)
Class 2: Receptor Transport ER-Golgi (Receptor cannot be transported out of ER)
Class 3: LDL binding (Error in LDL binding domain)
Class 4: Receptor clustering in coated pit(Receptors cannot cluster and localize correctly in coated pits)
Class 5: Discharge LDL in endosome recycle receptor (EGF like repeats-dissociation of receptor from LDL in endosome) |
|
|
Term
|
Definition
| Defect in p53 - Brain tumors and leukemia |
|
|
Term
|
Definition
|
|
Term
|
Definition
| Cancers that result from inactivation of sole remaining copy of tumor suppressor |
|
|
Term
|
Definition
Males have just one X-chromosome
Females have two X-chromosomes, but the second is inactivated
Father pass X chromosome to daughters, Y to sons
Y-chromosome initiates male dvelopment |
|
|
Term
| X-linked Recessive Inheritance |
|
Definition
No father-son transmission
Affected males usually have unaffected parents
Males are affected more frequently than females
Skips generations by transmission through carrier females. |
|
|
Term
| Duchenne and Becker Muscular Dystrophies |
|
Definition
X-linked recessive disease
Defect in dystrophin leads to muscle damage
Dystrohin gene is large target for new mutations
Wheelchair-bound by age 12, death before reproductive age. |
|
|
Term
| X-chromosome Inactivation |
|
Definition
Occurs after first week of embryonal development
Inactivated X-chromosomes condense at periphery of nucleus
Barr bodies make it easy to tell male from female cells |
|
|
Term
| DMD (Duchenne Muscular Dystrophy) Gene |
|
Definition
Mutation in DMD and BMD caused by mutation in this gene. Largest of the 30000 genes in the human genome
1/3 of cases due to new mutations
Prior to molecular diagnosis, carrier status was identified by measurement of creatine kinase levels which are elevated in 70% of obligate of carriers.
Molecular basis of most DMD is deletion of one or more exons. Duplications account for 6% and some translocations and point mutations-truncation/nonsense potein.
BMD caused by mutations that do not disrupt translational reading frame
Current prospective treatments include use of artificial chromosomes to deliver a good copy of DMD gene. |
|
|
Term
|
Definition
Vitamin D resistant rickets
Mutation in PHEX
Variable expressivity, bone deformities, short stature, dental anomalies, low renal phosphate absorption
X-linked Dominant disease
Males tend to have more sever bone abnormalities |
|
|
Term
|
Definition
Results from a defect in NEMO (NFkB essential modulator)
X-linked dominant
Rash in early infancy, skin erythema, vesicle and pustule progress to scarring hyperpigmentation and thinning of skin, mental retardation, microcephaly and defects in tooth development
Usually perinatally lethal in males |
|
|
Term
| Mitochondrial Inheritance |
|
Definition
Mutation rate about 10x higher than nuclear DNA. Present in multiple copie so mitochondrial disorder patients will have cells with varying fractions of mutant mtDNA molecules (heteroplasmy)
Affected female = all children affected
Affected Male = no children affected |
|
|
Term
| Leber's Hereditary Optic Neuropathy (LHON) |
|
Definition
Most prevalent mitochondrial disorder. Caused by mutation in ND1 gene (OXPHOS). Leads to rapid deterioration of optic nerve.
Mutations in mtDNA cause defect in ATP synthesis and increased oxidative stress in RGC's. |
|
|
Term
| Mitochondrial Heteroplasmy |
|
Definition
| Clonal mtDNA proliferation causes cells with varying levels of defective mitochondria. Disease and normal phenotype cells will both be present based on threshold for phenotype concentration |
|
|
Term
| Issues in Determining Mode of Inheritance |
|
Definition
Penetrance
Age of Onset
Inaccuracies in pedigree information (family secrets, paternity, miscarriage)
Sample swaps
Unidentifiable mutations |
|
|
Term
|
Definition
Genetic Information Nondiscrimination Act of 2008
Federal law protecting Americans from being treated unfairly because of differences in DNA that might affect their health. |
|
|
Term
|
Definition
| Loss of pregnancy from natural causes before the 20th week of pregnancy. Most miscarriages occur very early in pregnancy, in some cases before a woman even knows she is pregnant. |
|
|
Term
|
Definition
| Loss of pregnancy due to natural causes after the 20th week of gestation. Nearly 1 in 200 pregnancies in the US every year. In at least half of cases, no cause is known |
|
|
Term
| Estimated occurrence of chromosomal abnormalities |
|
Definition
|
|
Term
| Rate of sponataneous abortions |
|
Definition
50% first trimester
20% Second trimester |
|
|
Term
|
Definition
Describes the number and types of chromosomes
Constructed from live tissue induced to replicated, cell cycle arrested during metaphase and stained.
Banding pattern used to identify chromosomes and abnormalities |
|
|
Term
|
Definition
Number starts from the centromere
p is "short arm"
(chromosome number, p or q, # of division, # of band) |
|
|
Term
| Name the three common trisomy disorders. |
|
Definition
Trisomy 13- Patau syndrome
Trisomy 18- Edward syndrme
Trisomy 21- Down Syndrome |
|
|
Term
| Name the four common sex chromosome abnormalities. |
|
Definition
45, X- Turner Syndrome (female)
47, XXY- Klinefelter syndrome(duplicate X) (male)
47, XYY- Male
47, XXX- Female |
|
|
Term
| What are common structural alterations to chromosomes and what is the frequency of their occurance? |
|
Definition
Rearrangements, loss(deletion), or duplication of part of a chromosome.
Observed in 0.5% of pregnancies and 0.2% of live births |
|
|
Term
| What are the two processes that typically generate structural alterations? |
|
Definition
Incorrect double stranded DNA breaks
Non-homologous recombinations |
|
|
Term
|
Definition
Caused by deletion of distal short arm fo C5.
46,XY,del(5p)
Mental retardation. Clinical presentation is infant crying with the sound of a cat mewling
Microencephaly, hypertelorism, epicanthal folds, low set ears, micrognathia, mental retardation and heart defects. |
|
|
Term
| 22q11.2 Deletion syndrome |
|
Definition
DiGeorge sequence or velocardialfacial syndrome
Most common human microdeletion (originally too small to see on a karyogram) syndrome. 90% of patients have same 3 Mb deletion in 22q11.2region |
|
|
Term
|
Definition
22q11.2 deletion syndrome
Anaromly in the migration of neural crest cells
Structural or functional defects of the thymus, heart defects, reduced prathyroid function, secondary hypocalcemia. Most common phenotype is a congenital heart defect. |
|
|
Term
| Velocardiofacial syndrome |
|
Definition
22q11.2 deletion
Palatal abnormalities, some heart malformations, facial characteristics-narrow tall nasal root, smooth philtrum, developmental delay, learning disabilities and thymus malfunction |
|
|
Term
| Is genetic material lost in a reciprocal translocation? |
|
Definition
|
|
Term
|
Definition
|
|
Term
| Robertsonian translocation |
|
Definition
Between two acrocentric chromosomes (13,14,15,21, or 22) that fuse near the centromere.
Forms a derivative chromosome and the loss of short arms (because they're so small that no essential genetic information is there that life is possible)
Carrier is likely phenotypically normal but has a high risk of unbalanced gametes and offspring with unbalanced chromosomes (i.e. down syndrome) |
|
|
Term
|
Definition
Segment of a chromosome is removed from one and inserted in another.
Can be oriented in its original manner or it can be inverted (turned upside down)
Requires three chromosomal breaks and is rare. Carrier may be free of phenotype, but 50% risk of duplications or deletions in offspring. |
|
|
Term
| Paracentric vs Pericentric insertions |
|
Definition
| Paracentric does not include centromere and pericentric includes the centromere. |
|
|
Term
| Balanced vs Unbalanced alterations |
|
Definition
Balanced alteration - chromosomal alteration that does not change the overall amount of DNA
Unbalanced alteration-chromosomal alteration that does see an overall change in amount of DNA. |
|
|
Term
| How many pregnancies contain abnormal chromosomes? |
|
Definition
|
|
Term
| What are the top three chromosomal aberrations in live births? |
|
Definition
Trisomy 21
47, XXY, 47, XXX, 47, XYY
Balanced rearrangements |
|
|
Term
| Detection of chromosomal abnormlities |
|
Definition
Light and fluorescent microscopy (FISH), use of molecular genetics, use of microarray analysis.
Most commonly karyotype analysis. |
|
|
Term
| Problems of early growth/development. |
|
Definition
| Unless there is a convincing alternative explanation a chromosome analysis should be performed when problems with development arise. These include developmental delay, dysmorphic faces and mental retardation. |
|
|
Term
| Stillbirth/neonatal death |
|
Definition
| Chromosomal abnormality is present in around 10% of stillborn infants and infants who die in the neonatal window. Karyotyping can confirm or provide a diagnosis and may lead to karyotyping of parents and genetic counseling |
|
|
Term
| Fertility Problems: Clinical cytogenetics |
|
Definition
| In one parent is the cause of 3-6% of cases of recurrent miscarriage or infertility. |
|
|
Term
| Pregnancy with advance maternal age |
|
Definition
| Risk for aneuploidy increases. Fetal chromosome analysis should always be offered to pregnant women age 35 or older. |
|
|
Term
| What is a strong indicator for chromosomal influence? |
|
Definition
| Miscarriages or infertility |
|
|
Term
|
Definition
| Term to explain heritable states that do not depend on DNA |
|
|
Term
| How do epigenetic changes silence or activate chromosomal regions? |
|
Definition
| DNA methylation/demethylation and histone acetylation/deacetylation |
|
|
Term
|
Definition
Methylation of DNA occurs on cytosine residues in CpG repeats.
Methylation silences a genomic region |
|
|
Term
| Where are CpG repeats found? |
|
Definition
CpG islands upstream of genes. GpG islands are mostly non-methylated.
Repetitive DNA, including transposons In repetitive DNA, CpG repeats are mostly methylated.
About 70% of CpG's are methylated |
|
|
Term
|
Definition
hypermethylation: silences genes
Hypomethylation: increases or induces transcription |
|
|
Term
| Function of DNA Methyltransferases |
|
Definition
De-novo methylation DNMT3 - Part of developmental pathway. DNMT3 will methylate to shut down genes it doesn't need as it goes to a fully differentiated state.
Maintenance Methylation- DNMT1- Replicates pattern of methylation it already has. |
|
|
Term
|
Definition
Mapped to mutations in the gene for methyl-cytosine binding protein MECP2
Loss of transcriptional silencing
X-linked dominant (affected boys die shortly after birth)
Onset at age 6 to 18 months.
Autism-like symptos, repetitive teeth grinding and hand-wringing, motor problems, characteristic gait. |
|
|
Term
|
Definition
Acetylation of histones occurs in the tail region.
Acetylation of histones (on lysines) dicreases the affinity to DNA and de-acetylated histones bind more tightly to DNA (silences chromosomal regions) |
|
|
Term
|
Definition
Other histone modifications: Methylation, Phosphorylation, Ubiquitination
Modifications constitute a "histone code" imposed on the DNA |
|
|
Term
| Histone Acetylation/Methylation |
|
Definition
De-acetylated histones are methylated
Methylated histones bind HP-1 proteins
HP1 proteins bind histone methylase and the region of methylation spreads |
|
|
Term
|
Definition
Silences chromosomal regions by DNA methylation and histone deacetylation
Can be reverse, but in general is stable through somatic cell divisions |
|
|
Term
| When does imprinting occur? |
|
Definition
During gametogenesis to mark the parental origin of a chromosome
During development to permanently change the gene expression pattern of a cell line
Controlling state of imprinting can allow control (forward or backward) of cell differentiation |
|
|
Term
| What can imprinting identify in somatic cells of an adult? |
|
Definition
| Which copy of each chromosome came from which parent based on imprinting patterns. |
|
|
Term
| What's the point of imprinting research? |
|
Definition
Generation of pluripotent stem cells from accessible host tissue take skin biopsy and grow a new liver with no issues
Pharmaceuticals that can alter state of methylation to turn on tumor suppressors or turn off oncogenes. |
|
|
Term
| X-Chromosome Inactivation |
|
Definition
X-inactivation is mediated by an RNA transcript of the XIST gene.
Gene is only transcribed in the copy of the chromosome that is going to be silenced.
RNA product coats the whole of the chromosome from spreading out from the XIC (X-inactivation center)
DNA is methylated and histones de-acetylated causing chromosome to become dense "blob barr body.
Around 1/10 of the gene remains active
Daughter cells will have the same copy of the X chromosome silenced as the parent cell |
|
|
Term
| What is uniparental disomy? |
|
Definition
| Both chromosomes coming from one parent. |
|
|
Term
| What type of problems occur from uniparental disomy? |
|
Definition
|
|
Term
| Beckwith-Wiedemann Syndrome |
|
Definition
Can be caused by paternal uniparental disomy of Chromosome 11
Characterized by microcephaly, macroglossia, and umbilical hernia.
Overabundance of insulin-like growth factor 2 (IGF2) causes multiple orgain problems (liver, kidney, hypoglycemia)
Control of expression of IGF2 is mediated through elements in the IC1 region. |
|
|
Term
|
Definition
Deletion on paternal copy of Chromosome 15 or maternal uniparental disomy.
Excessive food seeking behavior.
Hypogonadism, mental retardation
Small hands and feet, hypotonia, facial features |
|
|
Term
|
Definition
Deletion on maternal copy of Chromosome 15 or paternal uniparental disomy.
Unusual facial features (large mandible, open mouth) Excessive laughter. Seizures, movement and gait disorders, Severe mental retardation, absence of speech. |
|
|
Term
| Lacking gene in Prader-Willi syndrome |
|
Definition
| SNURF-SNRPM Small nucleolar RNA (snoRNA) encded in an intron on chromosome 15 |
|
|
Term
| Missing gene in Angleman syndrome |
|
Definition
| UBE3A on chromosome 15 which is bilaterally expressed in most tissue except for the brain, where only th ematernal allele is expressed. |
|
|
Term
| DNA Silencing and Cancer - Hypomethylation |
|
Definition
Global hypomethylation of DNA outside of CpG islands is found in most cancers.
Hypomethylation of DNA causes genomic instability (elevated transposon activity and chromosomal abnormalities)
Genomic instability in turn causes cancer. (unclear which comes first) |
|
|
Term
| DNA Methylation in T-Cells |
|
Definition
Systemic Lupus Erythematosus (SLE) is caused by epigenetic changes in T-cells.
SLE is an autoimmune disease affecting females 8-10 times more frequently.
During SLE, antibodies against nuclear components are produced. SLE patients show global hypomethylation of the T-cell genome.
Treating T-cells with DNMT inhibitors causes SLE-like phenotypes. |
|
|
Term
| DNA Silencing and Cancer- Hypermethylation |
|
Definition
Hypermethylation of CpG islands in promoter can shut down tumor suppressor genes. Effect of silencing equals effect of null mutation.
10-15% of nonfamilial breast cancers due to hypermethylation of BRCA1 |
|
|
Term
| Therapeutic Interventions for Epigenetic Issues |
|
Definition
Hypermethylation can be reversed by DNMT inhibitor azacytidine (Treatment re-activates silenced tumor suppressor genes)
Excessive chromatin silencing can be reversed by HDAC inhibitors. |
|
|
Term
| What is the difference between the regulative phase and the mosaic phase in terms of cell loss? |
|
Definition
| Loss of a cell does not matter during regulative phase, but will lead to loss of tissue during mosaic phase. Can take a cell from the egg very early to see if the fertilized egg has a good or bad copy of the gene-using IVF up to the end of regulative phase. |
|
|
Term
| Formation of primitive streak. |
|
Definition
| Ectoderm cells invade space between epiblast and hypoblast. |
|
|
Term
| Axis Formation: Anterior/Posterior |
|
Definition
Ectodermal cells invade space between epiblast and hypoblast.
Groove is primitive streak - the anterior/posterior axis.
At the anterior end of the primitive streak is the node.
The gene NODAL (member of transforming growth factor beta superfamily)is required for formation of primitive streak. |
|
|
Term
| Axis Formation: Dorsal/Ventral |
|
Definition
| Dorsal develepment is induced by two gene products secreted from the node: NOG (was called 'noggin') and CHRD (was called chordin) |
|
|
Term
| Axis formation: Left/Right asymmetry |
|
Definition
| Asymmetric expression of SHH (sonic hedgehog) from the notochord (which will become spine) |
|
|
Term
|
Definition
Left/Right asymmetry development error.
Genetic cause unknown- autosomal recessive pattern, mostly asymptomatic- all organs are arranged in mirror image of 'normal' individual. |
|
|
Term
| In development, when are patterns developed? |
|
Definition
|
|
Term
| What genes are important for pattern formation and then talk about them. |
|
Definition
HOX genes.
Encode homeobox-binding transcription factors.
Each tissue expresses a different combination of HOX genes.
Tissue development depends on set of HOX genes expressed (Hox code) |
|
|
Term
|
Definition
Chromosomal location of the HOX gene clusters are related to pattern of expression during embryonal development.
There are 4 clusters of HOX genes
The pattern of HOX determines a cell's developmental fate. |
|
|
Term
| Five processes that drive development on a cellular level. |
|
Definition
Gene Regulation - Transcription Factors
Cell-cell signaling - Direct or indirect morphogens (through coherons or signaling molecules)
Development of cell shape/polarity- Gradient of proteins in cell
Movement and migration of cells
Programmed cell death (apoptosis) - development of eye. |
|
|
Term
|
Definition
Undifferentiated cells pass through a sequential, linear development process.
A cell destined to become a rod photoreceptor will first develop to resemble a ganglion cell, then differentiate to a cone photoreceptor, then a horizontal cell, then finally a rod photoreceptor.
Process is a one-way irreversible system that must occur sequentially. |
|
|
Term
| What factors push eye development in the correct direction? |
|
Definition
| Cell signaling, external signaling molecules, environmental factors (light), migration and regulation of gene expression by critical transcription factors. Regulated through methylation. |
|
|
Term
| Gene expression in eye development. |
|
Definition
| chx10 -> pax6 -> (crx or pax6 or chx10 or ax6 or brn3) |
|
|
Term
| What is type II aniridia a mutation in? |
|
Definition
|
|
Term
| Terms used to describe birth defects and dysmorphology. |
|
Definition
Cause of defect: Malformation, deformation, and disruption.
Mechanism by which one defect causes multiple abnormalities: Sequence and syndrome. |
|
|
Term
|
Definition
Result from an intrinsic abnormality in the developmental process.
Originates in the affected organ. |
|
|
Term
|
Definition
| Result from an extrinsic influence on development (e.g. lack of amniotic fluid) |
|
|
Term
|
Definition
| Result from the destruction of developing tissue (e.g. amputations by amniotic bands) |
|
|
Term
|
Definition
| Caused by a single defect that simultaneously affects the development of different tissues. |
|
|
Term
|
Definition
| Caused by a single defect that starts a cascade of events. |
|
|
Term
|
Definition
Causes a "U-shaped" primary cleft palate.
Collagen disorder+generalized growth retardation + neurogenic hypotonia + oligohydramnios -> mandibular hypoplasia -> robin sequence |
|
|
Term
| Time of Damage in development |
|
Definition
During first 1-4 weeks (blastogenesis): multiple major abnormalities in entire embryonic regions
From week 5 to week 8 (organogenesis): abnormalities in specific organs, single major anomalies
After week 9 (after organ formation): Mild effects |
|
|
Term
|
Definition
Association - group of birth defects that for unknown reasons often occur together
Vertebral defects, Anal atresia, Cardiac abnormalities, Tracheo-Esophagal fistula, Renal and Limb abnormalities
Defects thought to occur during blastogenesis phase of development
Maternal diabetes is risk factor |
|
|
Term
| Public Health Impact of Birth Defects |
|
Definition
| 2-3% of children are born with a birth defect. Account for 20% of infant mortality (40% if premature birth is included) |
|
|
Term
| What are the most common birth defects? |
|
Definition
Heart Defects
Pyloric stenosis
Neural tube defects
Orofacial clefts
Clubfoot |
|
|
Term
| How many birth defects have a contributable genetic cause been found for? |
|
Definition
|
|
Term
| why must development be tightly regulated? |
|
Definition
One extra round of cell division early in development is likely fatal.
An extra cell division late in development can lead to segmental overgrowth. |
|
|
Term
| Describe the robustness of development. |
|
Definition
Disturbances to normal process occur regularly and are countered by regulatory mechanisms
Raising mice under genetically identical conditions with a mutation encoding formin, 80% will not develop renal aplasia. Suggesting loss of formin can be tolerated and it's based on chance. |
|
|
Term
| Name a means of regulating gene expression during development. |
|
Definition
General transcription factors (e.g. CREB)
Specific transcription factos (e.g. HOX) |
|
|
Term
|
Definition
| Severe digital abnormalities in a patient heterozygous for both a novel missense mutation in HOXD13 and a polyalanine tract expansion in HOXA13 |
|
|
Term
| Rubinstein-Taybi Syndrome |
|
Definition
Defect in the general transcriptional activator in CREBP.
Affects the expression of many genes. |
|
|
Term
| Cell-to-cell signaling in development. |
|
Definition
Development dependent on signaling by diffusable factors.
Morphogens and other diffusable factors are secreted by cells and triger development in receptive cells.
Concentration gradient is established from originating cell to other cells in that region. |
|
|
Term
| Sonic Hedgehog (SHH) Morphogen |
|
Definition
SHH secreted from notochord and floorplate of neural tube
SHH gradient helps organizing the different cells in brain and spinal chord.
Defects in SHH signaling led to midline defects.
SHH must be cholesterylated-cholesterol synthesis problems have severe developmental phenotypes. |
|
|
Term
| Smith-Lemli-Optiz syndrome |
|
Definition
Caused by defect in cholesterol synthesis pathway
Autosomal recessive disease
Leads to severe congenital malformations in new borns.
In utero exposure to statins associated with birth defects. |
|
|
Term
|
Definition
SHH produced in notochord: high concentration- floor plate. low concentration - motor neurons.
Concentration also affects digit development. |
|
|
Term
|
Definition
| midline defects-cleft palates, central incisor. |
|
|
Term
| Cell Migration: LIS1 Mutation |
|
Definition
Development of CNS begins from the neural tube.
Neuronal stem cells divide and generate neuronal precursor cells.
Neuronal precursor cells have to migrate outward from the ventricle along a scaffold of glial cells.
Mutation in LIS1 gene interferes with migration and causes Lissencephaly (smooth brain) |
|
|
Term
|
Definition
Neuronal precursor cells migrate in waves along a scaffold of glial cells.
Problems with attching to spindles leads to incorrect placement. |
|
|
Term
|
Definition
True hermaphrodites have both testes and ovaries
Pseudohermaphrodites have either testes or ovaries-but doesn't match their genetic sex |
|
|
Term
|
Definition
In a male, if SRY region is deleted, the embryone will develop as an XY female
If SRY region is translocated to teh X chromosome, the embryo will develop as an XX male |
|
|
Term
| Sexual development pathway |
|
Definition
|
|
Term
| Female Pseudohermaphroditism: Adrenl Hyperplasia |
|
Definition
Masculinization of female babies.
Cholesterol converted to Androgens and male genitalia instead of cortisol and then aldosterone. |
|
|
Term
| Male pseudohermaphroditism |
|
Definition
| Lack of either SRY/TDF or Androgens leading to female external genitalia. |
|
|
Term
| Male Pseudohermaphroditism: Androgen insensitivy |
|
Definition
Feminization of male babies
Cholesterol goes to cortisol and aldosterone instead of androgens and male genitalia. |
|
|
Term
| Epigenetics of Development |
|
Definition
During development, cell lineages with a stable pattern of gene expression are established.
These permanent changes in gene expression are due to epigenetic factors (DNA methylation, histone deacetylation)
Problems with epigenetic programming of cells during development may lead to cancer later in life. |
|
|
Term
|
Definition
Any sequence variant present at a frequency of >1% in the population
OR
Any non-pathogenic sequence variant irrespective of freqency.
Could be single bases or whole genes or markers. |
|
|
Term
| Which genes have a high degree of polymorphism? |
|
Definition
|
|
Term
| Which genes have no polymorphisms? |
|
Definition
|
|
Term
|
Definition
6 million single-nucleotide polymorphisms between unrelated indivudals.
Normal genetic variation, usually do not cause disease but can be used as marker to identify disease loci
Used as "risk factors" |
|
|
Term
| Four assumptions of Hardy-Weinberg Principles |
|
Definition
Population is large
All genotypes have the same fitness
Mating is random
No influx or efflux of alleles |
|
|
Term
| Formula assumptions for Hardy-Weinberg equatin |
|
Definition
| There are only two alleles in the population. Good (p) and bad (q). p + q =1 |
|
|
Term
|
Definition
p + q = 1
Describes frequency of each allele
p^2 + 2pq + q^2 = 1
Describes frequency of genotypes |
|
|
Term
| What factors disturb the Hardy-Weinberg equilibrium? |
|
Definition
Genetic Drift (loss of rare alleles in small populations
Selection (loss of certain genotypes)
Gene flow (influx by migration)
Gene flow (mutations)
Nonrandom mating (consanguinuity) |
|
|
Term
| In an autosomal recessive disorder, what is an easy way of doing the Hardy-Weinberg calculations? |
|
Definition
| q^2 will equal frequency of disease in population. |
|
|
Term
| What is an easy way of doing X-linked recessive disease Hardy-Weinberg equations. |
|
Definition
| Allele frequency (q) is affected males/total males. |
|
|
Term
|
Definition
Selection reduce the frequencies of alleles that reduce fitness.
Dominant mutant alleles disappear quickly - if not constantly regenerated by new mutations.
Recessive alleles disappear slowly because thye hide in heterozygotes. |
|
|
Term
|
Definition
Heterozygotes have advantage (wider spectrum of enzyme activity)
some alleles provide advantage only in heterozygous state. |
|
|
Term
| How do CFTR mutations have positive selectivity? |
|
Definition
Typhoid fever selects for CFTR mutations (might have killed Pericles)
might make entry into cells difficult for typhoid pathogens |
|
|
Term
| Ellis-van Crefeld Syndrome |
|
Definition
Rare autosomal recessive disease
Caused by mutations in EVC genes
Parental consanguinity in 30% of cases |
|
|
Term
|
Definition
Ellis-van Crefeld Syndrome (EVS) prominent among the Amish in pennsylvania
Mutation can be traded to the founder of the population in the 18th century.
Community members are descendants of the founder-marriages become consanguineous.
Higher rate in Amish |
|
|
Term
| Concept of Race in Population genetics |
|
Definition
Race is a criterion for individualized treatments, forensic databases, etc.
Genome-wide analysis of poolymorphisms shows that 90% of variation is between individuals, not races. |
|
|
Term
|
Definition
Genetic polymorphisms are what determines susceptibility to disease, response to drugs.
Individualized medicine means using genetic information to predict responses.
Genotype is more telling than race. |
|
|
Term
|
Definition
| Polymorphic gene. Affect the individual response to vitamin D. |
|
|
Term
|
Definition
| With enough time, two markers will be randomly associated in the population providing there is enough distance for them to crossover. |
|
|
Term
|
Definition
| When equal allele amounts are not found in a population. |
|
|
Term
| What does Linkage disequilibrium show? |
|
Definition
Two markers can be separated by meisosis.
Over the course of many meiosises, there will be so many recombinations that the markers will be associated 50% of the time.
If they are associated more frequently, then the markers may be close together. |
|
|
Term
| How to map a disease locus on a chromosome with one marker. |
|
Definition
Expect to see A 50% and a 50%.
If mutation is close to a, marker 'a' will associate with the phenotype and affected individuals will be homozygous for a.
If far from 'a', then association of either marker is random. affected individuals will not be associated with any particular genotype. |
|
|
Term
| Problem with linkage disequilebrium analysis. |
|
Definition
Need to have a large number of affected individuals (around 10) from the same family to establish statistical significance.
Prediction of inheritance pattern needs to be accurate
Need to find enough polymorphic markers
Need to run all over genome.
Need to be lucky! |
|
|
Term
| Percent of population affected with a multifactorial inheritance disorder. |
|
Definition
|
|
Term
|
Definition
Defined as something that can be measured (height)
Usually are determined by many genes.
Alleles can be contributing or noncontributing to the trait. |
|
|
Term
|
Definition
Many genes and environmental factors are involved
Alleles can be contributing or noncontributing. |
|
|
Term
|
Definition
| Proportion of the population affected by the disease. |
|
|
Term
|
Definition
| Number of new cases in a given time divided by the size of the population |
|
|
Term
| Contributing vs causative alleles. |
|
Definition
| Contributing alleles have a much more subtle effect in mutations while causative mutation alleles will be the cause of the disease. |
|
|
Term
|
Definition
| number of mutant alleles before disease is diagnosed. |
|
|
Term
| Typical Changes of Risk: Multifactorial Birth Defects |
|
Definition
Risk for general population: 0.5%
One affected second degree relative: 0.7-2%
One affected first degree relative: 3-4%
Two affected first degree relatives: 5-8%
Three affected first degree relatives: 9-12%
Affected identical twin: 20-30% |
|
|
Term
| Implications of the Threshold Model |
|
Definition
Each birth of an affected child changes risk analysis: between parents there are enough contributing alleles to cause diseases. Birth of another affected child is more likely
Birth of a child of the less affected sex increases risk even more: Means that between parents there are enough contributing alleles to cross a higher threshold of liability. |
|
|
Term
|
Definition
Affects males more frequently than females. Threshold of liability is lower for males.
Presence of an affected female indicates the family has a large number of contributing alleles. Remodel disease risk.
Likelihood of affected child increases. |
|
|
Term
| Developmental Dysplasia of the Hip (DDH) |
|
Definition
Present in 1/1000 newborns
Female to male ratio of 5-9/1
Lower threshold for girls
Recurrence risk is higher when first affected child is a boy
Physical therapy to strengthen joint. |
|
|
Term
| Dissecting Environmental and Genetic contributions |
|
Definition
Observe concordance and discordance: how often does the trait occur in both members of a pair and how often not.
Twin studie: compare concordance in pairs of monozygotic and dizygotic twins
Adoption studies: Compare adopted children to their biological and adopted parents. |
|
|
Term
|
Definition
Monozygotic twins are genetically identical
Dizygotic twins share 50% of genes.
Both MZ and DZ grow up under similar circumstances.
If concordance in MZ is higher than DZ, trait has strong genetic component |
|
|
Term
|
Definition
(MZ concordance - DZ concordance) x 2
High heritability indicates trait is predominantly determined by genetic factors. |
|
|
Term
| Mapping of Complex traits |
|
Definition
Model-free linkage analysis- large scale analysis of genomic markers (preferable SNPs ) in affected families. Looking for markers that are linked to the disease.
Drawback: need large families and need tight diagnosis |
|
|
Term
| Determining and interpreting risk |
|
Definition
With no information you can inform patients about empirical risk (based on prevalence/incidence)
With details about affected family members you can give interpretation of relative risk ratio.
With some genetic data you can give interpretation of relative risk. |
|
|
Term
|
Definition
Incidence rate: how many cases are reported in a given time period
Prevalence rate: The proportion of the population that is affected at a given time
When the disease occur in a family, the prevalence and incidence changes for members of the family |
|
|
Term
| Relative risk ratio (lambda) |
|
Definition
A way to describe multifactorial disease.
= prevalence of disease in relative "r" of affected person/prevalence in general population |
|
|
Term
|
Definition
Correlation between mutant allele(s) and disease.
RRis a way to describe the disease association of an allele: how much more likely a carrier of the allele is to develope the disease than a non-carrier |
|
|
Term
| Characteristic Inheritance of Multifactorial Diseases |
|
Definition
Do not appear to follow a Mendelian pattern of inheritance
Show familial aggregation
Frequently show incomplete penetrance
Disease is much more common among close relatives of the proband than it is among less closely related persons |
|
|
Term
| Digenic Retinitis Pigmentosa |
|
Definition
Heterogeneou group of diseases. One subtype (RP7) is a slow onset degeneration f peripheral and night vision that may progress to loss of central vision
Some mutations in PRPH2 alone can cause ADRP
Other mutations occur in heterozygous digenic form with mutations in ROM1 cause slow onset Retinitis Pigmentosa
PRPH2 (6p21.1) - Arg13 Trp
ROM1(11q12.3) - Null Mutation
ROM1 mutation alone will not asue RP |
|
|
Term
| Identification of Type 2 Diabetes Susceptibility Loci |
|
Definition
Accounts for 90-95% of all diagnosed casses of diabetes.
Risk factors include old age, obesity, family history, impaired glucose tolerance, physical inactivity, and race/ethnicity |
|
|
Term
| What gene for type 2 diabetes was found in a genome wide association study? |
|
Definition
| TCF7L2-Transcription factor 7-like 2 gene |
|
|
Term
| What is molecular medicine? |
|
Definition
| The application of molecular biology, biochemistry, and genetics to the diagnosis and treatment of disease |
|
|
Term
|
Definition
Goal is to find defective genes or abnormal gene expression
Locating a disease gene-requires intense research (linkage analysis)
Identifying mutations in known disease genes.
Quantifying RNA Quantify/examine proteins |
|
|
Term
|
Definition
6.2 kb 1488 AA residues
27 exons over 188 kb
More than 1000 different mutations identified. 98% of mutations can be found by sequencing.
Most common mutations in caucasians: deltaF508 (class II), G542X (Class I), G551 D (Class 3) |
|
|
Term
|
Definition
| Largest gene in genome. Size makes it prone to new mutations. 1/3 of cases due to new mutations. |
|
|
Term
|
Definition
Extract DNA from tissue
Cut into convenient sized fragments
Run on a gel to separate fragments
Hybridize to custom sequence of your choice
Identify areas of hybridization through reporter system |
|
|
Term
| Southern vs Northern Blotting |
|
Definition
Southern Blot: Asks DNA questions. Is gene present? Is sequence truncated?
Northern Blot: Asks RNA questions. Is gene expressed in particular tissue? Is transcript length normal? Is 'normal' amount there? |
|
|
Term
|
Definition
| Molecular scissors that recorgnize and cut specific sequences of DNA |
|
|
Term
| Restriction Fragment Length Polymorphism |
|
Definition
| Cheap technique. Can analyze known mutations for very low cost, but you have to be lucky and have restriction site in the fragment of interest. |
|
|
Term
| Myotonic Dystrophy Detection |
|
Definition
| Myotonic dystrophy is autosomal dominant. Caused by triplet expansion of CTG repeats in 3' UTR of gene DM1. |
|
|
Term
|
Definition
Used to amplify DNA
Denature template DNA ate 94 C
Allow annealing of primers at 60 C
Polymerase synthesizes complementary strand at 72C
Repeat about 30 times. |
|
|
Term
| Reverse Transcriptase PCR |
|
Definition
PCR can be use to quantify RNA
Reverse transcriptase used to transcribe RNA into cDNA
cDNA serves as template for PCR reaction
more RNA present, the more DNA will be amplified.
Transcript lengths can be investigated |
|
|
Term
|
Definition
Accurate quantification of DNA and RNA can be achieved with quantitative PCR.
Amplification is monitored in real time.
See how many cycles are required to reach threshold levels of DNA |
|
|
Term
| Microarrays for Gene Expression Data |
|
Definition
Substrate: DNA Coding Sequence
Probe: RNA (cDNA) |
|
|
Term
| Microarrays for Mutations |
|
Definition
Substrate: Genomic DNA mutations
Probe: Genomic DNA |
|
|
Term
| Microarrays for linkage analysis data |
|
Definition
Substrate: SNPs
Probe: Genomic DNA |
|
|
Term
|
Definition
mRNA from sample 1 + mRNA from sample 2
Convert to cDNA and label
Mix and hybridize to expression array
Spots indicate which probes hybridize
Yellow-both, red-mainly sample 1, green, mainly sample 2, blue- none. |
|
|
Term
| Applications for Genetic Information |
|
Definition
Pharmacogenomics
Prenatal diagnosis
Prevention |
|
|
Term
|
Definition
Problem: Individual drug responses are hard to predict
Assumption: Genetic Individuality is what determines drug response
Goals: Find allele linked to drug response, predict response from genotype, find individual drug treatment plan |
|
|
Term
|
Definition
Warfarin is most commonly used oral anticoagulant
Warfarin inhibits vitamin K epoxide reductase (VKORC1)
Polymorphism in VKORC1 affects sensitivity
Warfarin is metabolized by a P450 enzyme (CYP2C9)
Polymorphism in CYC2C9 also affects sensitivity |
|
|
Term
|
Definition
Most important tools are antibodies
Antibodies bind to antigens with high specificity
Antibodies can be labeled. Detection of label reveals the presence of antigen |
|
|
Term
|
Definition
1. Purify protein of interest
2. Inject rabbit with protein solution
3. After several days, withdraw blod.
4. Rabbit serum contains (among others) antibodies against protein of interest. |
|
|
Term
|
Definition
Good for detecting small amounts of antigen and high throughput.
Antibody vs protein of interest.
Antibody-coated well. Add antigen. Antigen binds to antibody (antigen samples immobilized). Add enzyme-linked specific for antibody (antibody vs protein of interest with reporter tag). Add substrate and develop color or fluorescence. |
|
|
Term
|
Definition
Good for detecting presence of antibodies.
Antigen coated well (antigen attached to a substrate). Add Antibody solution (probe). Antibody binds to antigen. Add enzyme-linked antibody (secondary antibody recognizes human antibodies with reporter tag). Add substrate and develop color or fluorescence. |
|
|
Term
|
Definition
Determine protein expression profile. Can provide much informtion about tissue/cell lines/biopsy.
Separate protein extrats by eletrophoresis.
Transfer proteins to membrane.
Add enzyme linked specific antibody.
Antibodies bind to antigen.
Detect label (fluorescence, color or radioactivity) |
|
|
Term
| What type of diseases are gene therapy possible for? |
|
Definition
| ONLY with recessive diseases |
|
|
Term
| Safety concerns of gene therapy |
|
Definition
Massive immune responses
Transformation of 'cured'cells into tumor cells |
|
|
Term
| Treatment of ADA deficiency |
|
Definition
1990-1995
Aim was to cure children of SCID caused by defects in the ability of cells in nucleotide salvage
Impairs tissues such as immune stem cells that require rapid expansion (proliferation) resulting in a deficiency of B and T cells. Recurrent bacterial, fungal, and viral infecions. |
|
|
Term
| Gene Therapy: ADA deficiency |
|
Definition
ADA gene + modified retrovirus -> retrovirus transfers ADA genes into T-cells isolated from patients.
Cells selected and grown in culture.
Cells are reimplanted. |
|
|
Term
| Difficulties with ADA therapy |
|
Definition
9/11 patients recovered
2 developed leukemia as a result of insertional activation of LMO2 oncogene. Clinical trials halted |
|
|
Term
| How trials are changed after little success |
|
Definition
Different vectors
Greater care of delivery/quantity
More in depth studies in animal models with long term follow up |
|
|
Term
|
Definition
Disease: Tumors and Aids
Stability of Expression: Stable (random insertion into genome) |
|
|
Term
|
Definition
Disease: Cold, conjuctivitis and gastroenteritis
Stability of Expression: No integration. Expression lost in 3-4 Weeks |
|
|
Term
| Gene therapy: Adeno-associated virus |
|
Definition
Disease: No known disease
Stability of Expression: Stable |
|
|
Term
| Gene Therapy: Herpes simplex virus 1 (HSV-1) |
|
Definition
Disease: mouth ulcers, genital warts, encephalitis
Stability of Expression: Stable, maintained outside of the chromosome |
|
|
Term
| Gene Therapy: baculovirus |
|
Definition
Disease: None in mammals
Stability of Expression: Unstable |
|
|
Term
|
Definition
Retrovirus
Adenovirus
Adeno-associated virus
Herpes simplex virus 1 (HSV-1)
Baculovirus |
|
|
Term
| Factors in choosing viruses for gene therapy |
|
Definition
Dosage (how much needed)
Serotypes (more effective/less effective)
Serotypes (cell specific)
Carrying capacity |
|
|
Term
| Non-viral methods of DNA Transfer |
|
Definition
Liposomes
Naked DNA
Complexed DNA
Artificial chromosomes |
|
|
Term
| DNA transfer through liposomes |
|
Definition
Lipid bubbles containing DNA
Can accommodate large DNA fragments, can easily enter cells, but slow to get into cells and low chance of incorporation into genome. |
|
|
Term
| DNA transfer through 'naked' DNA |
|
Definition
DNA can be blasted into cells.
Easy to prepare; cheap.. But only cells that are accessible, low incorporation rate into genome. |
|
|
Term
| DNA transfer through complexed DNA |
|
Definition
DNA attached to a carrier substance
DNA becomes compacted and easily transferred into cells. Low genomic incorporation rate |
|
|
Term
| DNA transfer through artificial chromosomes |
|
Definition
Constructed with DNA of your choice
Can accommodate very large genomic chunks (good for genes such as dystrophin)
Can be difficult to get into cellsa nd danger may come from unpredictable chromosomal events. |
|
|
Term
| RNA Inteference: Strategy |
|
Definition
Identify gene/mutation, design ds RNA against unique transcript
Get interfering RNA into a cell that suffers from the effects of gene overexpression.
Could be done with methods of gene therapy - construct vector that expresses RNAi |
|
|
Term
| Microarrays- Tumor Profiling |
|
Definition
Can map gene expression pattern mostly associated with poor outcome and gene expression pattern mostly associated with good outcome.
Understand progress of disease, understand mechanism, identify significant changes that affect prognosis, generate targets for interventions. |
|
|
Term
| Antibodies Targeting Tumor Cells |
|
Definition
25% of breast cancers overexpress the HER2 (ErbB2) receptor.
Herceptin is a monoclonal antibody thatbinds to receptor.
mutation -> Increased ErbB2 synthesis -> exposure of ErbB-2 protein on cell surface -> binding of Herceptin to surface of tumor cell -> receptor is internalized |
|
|
Term
|
Definition
Monoclonal Antibody
Rituxin
Non-Hodgkin lymphoma
Approved 1997 |
|
|
Term
|
Definition
Monoclonal Antibody
Herceptin
Breast Cancer
Approved 1998 |
|
|
Term
|
Definition
Monoclonal antibody
Mylotarg
Acute myelogenous leukemia (AML)
2000 |
|
|
Term
|
Definition
Monoclonal antibody
Campath
Chronic lymphocytic leukemia (CLL)
Approved 2001 |
|
|
Term
|
Definition
Monoclonal Antibody
Zevalin
Non-Hodgkin Lymphoma
Approved 2002 |
|
|
Term
|
Definition
Monoclonal Antibody
Bexxar
Non-Hodgkin Lymphoma
Approved 2003 |
|
|
Term
|
Definition
Monoclonal Antibody
Erbitux
Colorectal cancer
Head and Neck Cancers
Approved 2004 and 2006 |
|
|
Term
|
Definition
Monoclonal antibody
Avastin
Colorectal Cancer
Approved 2004 |
|
|
Term
| Leber Congenital Amaurosis: Cardinal Features |
|
Definition
Profound photoreceptor dysfunction in first two years of life
Congenital nystagmus
Severely reduced vision
Attenuated or non-recordable ERG
Pigmentary retinopathy - invasion of pigmented cells into the neural retina |
|
|
Term
|
Definition
Optical coherence tomography shows that the lamina of the neural retina is intact in RPE65 mediated LCA
Retina is described as structurally intact, but electrically silent.
Mutations in RPE65 prevent the recycling of the chromophore essential for formation of visual pigments
Supplying the correct tissue (RPE cells) with a good copy of the gene may restore function. |
|
|
Term
| What is the name of the dog who was able to cure LCA with gene therapy? |
|
Definition
|
|
Term
| Recurrence risk of down syndroe? |
|
Definition
|
|
Term
| Achondroplasia: Disease Overview |
|
Definition
Autosomal Dominant
Defect in Bone Growth
New mutations, fitness, dominant negative allele, mutation hotspot |
|
|
Term
| Cystic Fibrosis (CF): Disease Overview |
|
Definition
Autosomal Recessive
Defective Chloride Channel
Allele heterogeneity, modifier Loci |
|
|
Term
| Duchenne Muscular Dystrophy (DMD): Disease Overview |
|
Definition
X-Linked Recessive
Defect in dystrophin
New mutations, large target |
|
|
Term
| Ehlers-Danlos Syndrome: Disease Overview |
|
Definition
Autosomal Recessive and Autosomal Dominant
Collagen Disorder |
|
|
Term
| Familiar Hypercholesterolemia: Disease Overview |
|
Definition
Autosomal Dominant
Defective LDL receptor
Allele heterogeneity |
|
|
Term
| Fructose-1,6-bisphosphatase deficiency: Disease Overview |
|
Definition
Autosomal Recessive
Fasting Hypoglycemia |
|
|
Term
| Glucose-6-phosphate dehydrogenase deficiency: Disease Overview |
|
Definition
X-linked Recessive
Sensitivity to H2O2-generating agents and fava beans. |
|
|
Term
| Glycogen storage disorders: Disease Overview |
|
Definition
Autosomal Recessive
Hypoglycemia, Accumulation of Glycogen |
|
|
Term
| Huntington Disease (HD): Disease Overview |
|
Definition
Autosomal Dominant
Neurological Disorders
New mutations, triplet expansion, anticipation |
|
|
Term
| Leber's Hereditary Optic Neuropathy (LHON): Disease Overview |
|
Definition
Mitochondrial Inheritance
Defect on mitochondrial DNA
Heteroplasmy |
|
|
Term
| Neurofibromatosis (NF): Disease Overview |
|
Definition
Autosomal Dominant
Multiple tumors
New mutations, variable expressivity, pleiotropy |
|
|
Term
| Osteogenesis Imperfecta: Disease Overview |
|
Definition
Autosomal Dominant
Defective type I collagen
Dominant negative allele, allele heterogeneity |
|
|
Term
| Phenylketonuria: Disease Overview |
|
Definition
Autosomal Recessive
Tyrosine Metabolism
Newborn Screening |
|
|
Term
| Sickle-Cell Anemia: Disease Overview |
|
Definition
Autosomal Recessive
Hemolysis |
|
|
Term
| Sucrase-Isomaltase deficiency: Disease Overview |
|
Definition
Autosomal Recessive
Sucrose/glucose polymer intolerance |
|
|
