PHRM 824 Exam 5 Flashcards
Define autosomal dominant
- a single mutant allele from an affected parent is transmitted to an offspring regardless of sex
- 50% chance of passing the trait to each child
- unaffected relatives/siblings do not transmit the disorder
- in many conditions, the age of onset is delayed, and the signs and symptoms of the disorder do no appear until later in life
List an example of an autosomal dominant disorder:
Huntington disease: neurogenerative disorder
Define autosomal recessive
- autosomal recessive disorders are manifested only when both members of the gene pair are affected (homozygous)
- same probability for males and females
- all children of an affected parent are carriers
- age of onset is early in life
- symptoms are more uniform
List an example of an autosomal recessive disorder
Cystic Fibrosis - causes lung and pancreatic disease
Sickle cell disease - red blood cell defect
Tay-Sachs - severe mental and physical deterioration beginning in infancy
List an example of an x-linked recessive disorder.
Hemophilia A – joint bleeding, muscle hematoma, soft tissue bleeding
Define x-linked recessive
- 50% chance of passing the gene to their sons and daughters
- daughters are unaffected
- males who receive the gene are affected
- affected males pass the mutant to all daughters, but not to sons
Define penetrance
- a 50% penetrance indicates that a person who inherits the defective gene has a 50% chance of expressing the disorder.
Define expressivity
- mutations in a gene can give rise to different outcomes in different people
- ranges from complete to minimal
- affected by: other genes, exposure to harmful chemicals or conditions, environment, age
What is a genetic variant?
- a change in the DNA sequence that makes up a gene
How are genetic variants categorized?
- pathogenic
- likely pathogenic
- uncertain significance
- likely benign
- benign
Define pathogenic variants
- responsible for causing disease
- well supported by scientific research
- often referred to as mutations
Define likely pathogenic variants
- probably responsible for causing disease
- not enough scientific research to be sure
Define uncertain significance variants
- not confirmed to cause disease
- not enough scientific research
Define likely benign variants
- probably not responsible for causing disease
- not enough scientific research to be sure
Define benign variants
- not responsible for causing disease
- strong scientific research to rule out link to disease
Define likely benign variants
- probably not responsible for causing disease
- not enough scientific research to be sure
How do genetic variants relate to mutations?
- mutations lead to variants
What is a silent mutation?
- has no effect
What is a nonsense mutation?
- type of substitution variant in which a single nucleotide is replaced to where the sequence now codes for a stop codon in the incorrect place
- shortening of the protein
What are the three types of mutations that cause autosomal dominant disorders?
What is a missense mutation?
- type of substitution variant in which a single nucleotide is replaced
- results in an incorrect amino acid in the protein product – may be malfunctioning
Which kind of mutations can cause recessive disorders?
What are insertions/deletions?
- these are frameshift mutations
- insertion or deletion of one or two base pairs alters the reading frame of the DNA strand
What is karyotype analysis?
- A karyotype is a photographic representation of a stained metaphase spread in which the chromosomes are arranged in order of decreasing length
- The use of banding allows certain identification of each chromosome
How can karyotype analysis be used to diagnose genetic diseases?
- It is used to detect abnormalities in chromosome number and structure
Which mechanisms lead to abnormalities in chromosome number?
deletions, monosomy, trisomy
What genetic changes cause Down Syndrome?
- they have trisomy 21, so their chromosome count is 47
- common characteristics: excess skin on back of neck, transverse palmar crease, folder or dysplastic ear
What genetic changes cause Turner Syndrome?
- monosomy X
- characteristics: growth retardation, swelling of nape of neck, lymphedema of hands and feet, in adolescence: affected girls don’t develop secondary sex characteristics
What is the inheritance pattern for mitochondrial mutations?
- maternal inheritance
- mitochondria are only inherited from mother
- only daughters may transmit mutations in mitochondrial genes to progeny
What is the inheritance pattern for imprinting defects?
- parent of origin transmission
- some regions of DNA are turned off in the copy received from the mother or the father
- if a region that is turned off in the maternal copy is mutated in the paternal copy, genes in that region will not be expressed
Name and explain an example of triplet repeat diseases.
Fragile X syndrome: mutation is characterized by a long repeating sequence of 3 nucleotides
- loss of function of FMR1 –> mental retardation
- characteristics: elongated face, protruding ears, low muscle tone
- primarily affects males
Name and explain an example of mitochondrial mutations.
- diseases caused by mutations in mitochondrial genes are rare
- affect organs that depend most on oxidative phosphorylation (skeletal muscle, heart, brain)
What is the inheritance pattern of triplet repeat diseases?
- first generation: all sons are normal and all females are carriers
- during oogenesis in the carrier female, premutation expands to full mutation —>
- next generation: all males who inherit the X with the full mutation are affected —– only 50% of females who inherit the full mutation are affected
Name and explain an example of imprinting defects.
Prader-Willi Syndrome:
- region of chromosome 15 deleted inherited from father
- mental retardation, short stature, hypotonia, obesity, small hands and feet, hypogonadism
Angelman Syndrome:
- region of chromosome 15 deleted inherited from mother
- mental retardation, ataxic gait, seizures, inappropriate laughter
What are the three fundamental principles of carcinogenesis?
1) genetic changes (mutations) lie at the heart of carcinogenesis
2) Two major classes of genes are the targets of this damage (oncogenes + tumor suppressor genes)
3) Carcinogenesis is often a multistep process with multiple genes involved
What are the two major classes of genes that are the targets of genetic damage during carcinogenesis?
- oncogenes: genes that encode proteins that promote cancer —-> Gain of function mutations constitutively stimulate cell proliferation
- tumor suppressor genes: genes that encode proteins that inhibit cancer —–> Loss of function mutations cause a loss of inhibition of cell proliferation
Explain the two-hit hypothesis for tumor suppressor genes.
- The malfunction of tumor suppressor genes may require “two hits” to contribute to total loss of function
- The first hit may be a point mutation in an allele of a particular chromosome
- Later, the second hit occurs that involves the companion allele of the gene
Why does cancer risk increase with age?
- accumulation of somatic mutations
- decline in immune function
How do inherited mutation in DNA repair genes contribute to increased cancer risk?
- the loss of DNA repair causes increased mutation rate and increased tumor incidence
How do environmental factors increase DNA damage?
sunlight, asbestos, cigarette smoking all increase mutations
List the six hallmarks of cancer cells.
1) self-sufficiency in growth signals
2) insensitivity to anti-growth signals
3) Evasion of apoptosis
4) Limitless replicative potential
5) sustained angiogenesis
6) tissue invasion and metastasis
Explain cancer cells that have self-sufficiency in growth signals
Example: Model for action of RAS genes:
- When a normal cell is stimulated through a growth factor receptor, inactive RAS is activated to a GTP-bound state.
- Activated RAS recruits RAF-1 and stimulates the MAP-kinase pathway to transmit growth-promoting signals to the nucleus
- MYC gene is one of several targets of the activated RAS pathway. The mutant RAS protein is permanently activated because of inability to hydrolyze GTP, leading to continuous stimulation of cells without any external trigger
- The anchoring of RAS to the cell membrane is essential for its actions
Explain cancer cells that display insensitivity to anti-growth signals
- cancer may arise through loss of expression (mutation) of growth inhibitory proteins
- RB exerts antiproliferative effects by controlling G1-to-S transition in the cell cycle
- Cells are arrested in G1
- Loss of cell cycle control is fundamental to malignant transformation
Explain how cancer cells evade apoptosis
- Disruption of apoptotic pathways prevents cell death upon DNA damage or cell cycle checkpoint activation
- p53 is a tumor suppressor
- activated p53 drives transcription of p21 that prevents RB phosphorylation –> causes a G1-S block –> pause in cell cycle allows for damage repair
- If the damage can’t be repaired, p53 induces apoptosis
- loss of p53 –> evading apoptosis
- loss of p21 –> DNA won’t be able to get repaired
Explain how cancer cells sustain angiogenesis
- Hypoxia triggers angiogenesis through the actions of HIF1a
- Mutations to VHL (a tumor suppressor gene) prevents HIF1a from being recognized. This prevents HIF1a from being destroyed, so angiogenesis continues.
- Tumor cells produce VEGF to promote angiogenesis
Explain the limitless replicative potential of cancer cells
- tumor cells overexpress telomerase –> leads to cell immortalization
Explain how cancer cells invade tissues and metastasize
1) Adhesion and invasion of basement membrane beneath tumor
2) migration through extracellular matrix
3) Invasion of vascular basement membranes and vascular ingress (intravasation)
4) Travel via the vasculature
5) Adhesion to basement membrane at destination
6) Invasion of vascular basement membrane and vascular exit (extravasation)
7) Migration through extracellular matrix
8) Formation of metastatic deposit and cell proliferation
How is the cell cycle regulated and monitored?
- R point: critical time point when cells decide whether or not to enter the cell cycle
- G1/S Checkpoint : check for DNA damage
G2/M Checkpoint: check for damaged or unduplicated DNA - driven by cyclins and CDK
How can genetic alterations of the tyrosine kinase signal transduction pathway lead to to cancer?
- RAS is the most commonly mutated proto-oncogene in human tumors
- RAS gets trapped in activation and the cell is forced to continuously proliferate
How do tumors induce angiogenesis?
tumor cells produce VEGF
How does inflammation increase cancer risk?
inflammation results in hyperplasia and DNA damage as a result of ROS and RNS produced by immune cells
How do viruses cause cancer?
- integration into the genome (retroviruses) can cause modulation of oncogenes or tumor suppressor genes
Explain the sequence of genetic changes associated with colon carcinogenesis.
- Normal colon: Loss of APC gene (first hit)
- Mucosa at risk: DNA methylation –> inactivation of normal alleles (second-hit)
- Adenomas: GOF of RAS; LOF of SMAD2+4 suppressor genes
- Carcinoma: Mutation of p53 and more genetic changes
Define uncertain significance variants
- not confirmed to cause disease
- not enough scientific research
