Foundations 1 Week 4 Flashcards
What is the inheritance pattern of Neurofibromatosis Type I, and why is the NF-1 gene so susceptible to mutations?
Autosomal Dominant inheritance with 100% penetrance
50% of cases are a result of new mutations in the NF-1 gene – which is common due to NF-1’s large size (>350kB) and high rate of mutations (1 in 10,000 bases).
Lecture: Topics in Genetics
Objective 1: Describe the characteristic features and genetic cause of neurofibromatosis, type 1.
What cardinal property distinguishes benign growth (e.g., nevus/mole) from malignant cancer (e.g., melanoma)?
Metastasis – spread of tumor to a distant site
Four characteristics serve to distinguish between benign and malignant neoplasms (Degree of Differentiation, Rate of Growth, Local Invasion, and Metastasis), but only metastasis is seen solely in malignant neoplasms.
Lecture: Molecular Basis of Cancer
Objective 2: Explain the intrinsic properties of malignant neoplasms that distinguish them from benign neoplasms.
What are two mechanisms by which euchromatin (actively transcribed chromatin) can become heterochromatin (repressed)?
DNA methylation (at CpG islands) and Histone Deacetylation
DNA methylation prevents binding of transcription factors. Histone deacetylation reduces the negative charge provided by OCH3-(acetyl) groups, allowing negatively charged DNA to bind coil more tightly around the nucleosome. Both epigenetic mechanisms reduce active transcription of a particular stretch of chromatin.
Lecture: Epigenetics
Objective 2: Describe the currently known categories and mechanisms of epigenetic gene regulation
Ataluren is a small molecule approved in Europe for treatment of a specific type of Duchenne Muscular Dystrophy. What is the etiology of DMD that Ataluren is targeted towards and how does it work?
DMD caused by nonsense mutations – Ataluren is a “Read-through drug”
A subset of DMD is caused by nonsense mutations, mutations that lead to an aberrant stop codon. While this can be a result of single base substitutions, insertions, or deletions, all nonsense mutations result in a stop codon that leads to nonsense mediated decay of mRNA or targeting of the protein transcript to Endoplasmic-Reticulum Associated Degradation. Ataluren, and other “Read-through” drugs, allows stop codons to be ignored which may preserve protein function in disorders with premature stop codons.
Lecture: Novel Treatments for Genetic Disorders
Objective 1: Describe how nonsense mutations cause disease and how they may be treated.
- A patient is brought to the ER with bright red skin following inhalation of an unknown gas, and you notice the patient’s breath has a characteristic bitter almond odor. Quickly realizing that the patient most likely has ________, you begin treatment with nitrites followed by thiosulfate. What electron transport chain complex was inhibited by the inhaled gas?
Cyanide Poisoning – inhibits Complex IV (Cytochrome C Oxidase).
Breath smelling like bitter almonds is characteristic of cyanide poisoning and can distinguish between cyanide and carbon monoxide poisoning. Cyanide, as well as Carbon Monoxide, bind to iron in cytochrome oxidase, halting the ETC at the final step where electrons are transferred to oxygen to form water.
Lecture: Mitochondria and Oxidative Phosphorylation
Objective 5: Identify medically relevant inhibitors of oxidative phosphorylation
Explain how heteroplasmy is related to the wide variation in phenotype, despite having the same mutation, seen with mitochondrial disease.
Heteroplasmy is defined as the presence of mutated and unmutated mitochondrial DNA within a single cell or mitochondrion (similar idea to mosaicism). This is due to the fact that each mitochondrion contains multiple copies of mtDNA, and each cell contains many mitochondrion. As a result, two patients with the same mtDNA mutation (e.g., from the same family) can present very differently depending on the proportion of affected mitochondria present within their cells.
Lecture: Mitochondrial Genetics and Disease
Objective 2: Define heteroplasmy and explain its relationship to the threshold effect, and the phenotypic variability in mitochondrial disorders, even within a single family.
Prader-Willi Syndrome and Angelman Syndrome both most commonly result from a 15q11-13 deletion, yet the two syndromes have unique manifestations. Explain how these two syndromes provide evidence for the differential epigenetics between maternal and paternal chromosomes.
Prader-Willi syndrome is due to the deletion of the paternal chromosome (Prader sounds like Father, or the P in Prader can help remind you that this is due deletion of paternal chromosome 15). In contrast, Angelman Syndrome is due to deletion of maternal chromosome 15. If there was no difference in maternal and paternal chromosomes at this particular locus, then either the other chromosome could substitute for the mutated chromosome (no disease would be present) or the two syndromes would have the same presentations (an example of haploinsufficiency). However, the syndromes exist and do NOT present similarly, thus providing evidence for some difference between maternal and paternal chromosomes that is not simply due to the genetic sequence. This is further supported by the presence of differential banding (representing euchromatin and heterochromatin – both of which are affected by epigenetic modifications) between both chromosomes.
Lecture: Epigenetics, Imprinting, and Uniparental Disomy
Objective 3: Describe the effect of the parent’s sex on the expression of imprinted genes.
