Lecture 4: Genetic Mutations/Disorders Flashcards
Autosomal Mutations occur in … cells and are not …. , while Germline mutations occur in … cells and may be …
Autosomal Mutations occur in SOMATIC cells and are not INHERITED, while Germ-line mutations occur in GAMETIC cells and may be INHERITED
When naming mutations/variants what is denoted as the +1 position?
The “A” of the Start Codon (AUG)
Describe the Intron Mutation–> c89+21
c89 refers to the last exon nucleotide (Exon 89) and the mutation occurs 32 nucleotides into the Intron
How would you write the Amino Acid mutation Tryptophan to Lysine at the 108th position (in AA single abbreviation)?
P. W108K
What type of mutation is P. Asp47X
Missense Mutation (X refers to an improper STOP codon)
What are the three STOP codons
1) UGA 2) UAA 3) UAG
In a …. Insertion/Deletion the Open Reading Frame (ORF) is changed, whereas in a …. Insertion/Deletion the ORF is not changed
Frameshift; Non-Frameshift
What is the single point mutation of Sickle Cell Anaemia?
P. G6V of the Beta-Subunit of Haemaglobin
True or False: A Missense Mutation results from an early Stop Codon, while a Non-Sense Mutation results from a Substitution of different AAs.
False; A NON-SENSE Mutation results from an early Stop Codon, while a MISSENSE Mutation results from a substitution of different AAs.
Define Non-Sense Mediated Decay
A Non-Sense mRNA mutation is recognized by a surveillance pathway within the cell and the Non-sense mRNA is degraded prior to translation.
What two nucleotides does an Intron typically start and end with?
Introns typically start with “GU” and end in “AG”
What mutations cause Neurofibromatosis Type 1 (NF1) and/or Menkes Disease?
Splice Site Mutations
True or False: Splice Site Mutations lead to 1) New Splice Sites 2) Unmasking of Cryptic Splice Sites
True
A missense mutation of the …. gene is responsible for Achondroplasia (i.e. “Dwarfism”).
FGFR gene on Chromosome 4 (c. 113 G > A)
The FGFR gene is an example of a (Gain/Loss) of Function mutation as it (Over-inhibits/Under-inhibits) Cartilage formation, leading to Achondroplasia
Gain of Function Mutation; Over-inhibits Cartilage Formation
True or False: An individual homozygous for the gene mutation of Achondroplasia is even shorter that an individual that is only heterozygous?
False; The homozygote form of Achondroplasia (both mutant FGFR gene copies) is lethal.
What three organ systems does Marfan Syndrome affect?
1) Skeletal 2) Occular 3) Cardiovascular
What is Pleitropy? What disease/syndrome is an example of Pleitropy?
One gene affects multiple organ systems in the body (Ex. Marfan Syndrome)
What phenotype does someone with Marfan Syndrome have?
Extremely tall, potentially dislocated lens of the eye and aortic dissection
The … gene on Chromosome 15 is responsible for Marfan Syndrome and is an example of a (Gain/Loss) of Function mutation.
The FB1N gene on Chromosome 15 is responsible for Marfan Syndrome and is an example of a LOSS of Function mutation.
How does a mutation in FB1N lead to Marfan Syndrome?
- FB1N encodes for Fibrillin Protein which is a major component of Microfibrils
- Microfibrils 1) Provide Structure 2) Control free TFGBeta
- TGFBeta is a potent Growth Factor and in excess can lead to the severe problems associated with Marfan Syndrome
Ex. Extremely tall, Aortic Dissection and Lens of the Eye Dislocations
True or False: An increase in Maternal age leads to an increase in De Nova Mutations for Marfan Syndrome and Achondroplasia
False; An increase in PATERNAL age leads to an increase in De Nova Mutations for Marfan Syndrome and Achondroplasia
True or False: The FB1N gene is a Loss of Function mutation and the FGFR gene is a Gain of Function mutation
True; FB1N mutation= Loss of Function= Marfan Syndrome
FGFR mutation= Gain of Function= Achondroplasia
What are three clinical signs for diagnosis of Cystic Fibrosis (CF) in babies?
1) Meconium Illeus (Inability to pass Black Meconium)
2) Poor Fat Absorption (Leads to a Deficiency in Pancreatic Enzymes)
3) Pulmonary Problems (#1 reason for deaths)
What is the gold-standard test to diagnose Cystic Fibrosis?
Sweat Test= Na+ and Cl- levels in the Sweat are way too High
What is the mutated gene responsible for Cystic Fibrosis?
CTFR gene
True or False: In the Airway Epithelium, CTFR encodes a normal ion channel that pumps Cl- ions into the Extracellular Fluid and NA+ ions into the cell
True
True or False: In the Sweat Glands, CTFR encodes a normal ion channel that pumps Cl- ions and Na+ ions both out of the cell
False; In the Sweat Glands, CTFR encodes a normal ion channel that pumps Cl- ions and Na+ ions both INTO the cell
What is the mechanism of disease for Cystic Fibrosis (CF) in Airway Epithelium when the CTFR gene is mutated?
- The CTFR gene typically encodes for an aberrant ion channel which doesn’t let Cl- leave to the Extracellular Fluid (ECF)
- Causes NA+ to enter the cell in excess
- Water tries to balance the High Osmolarity by entering the cell
- Loss of water causes thickening of Mucous in the ECF
True or False: There is great variation in Clinical Symptoms/Severity of Cystic Fibrosis due to multiple CFTR mutations
True
What is the major mutation associated with Cystic Fibrosis?
In-Frame deletion of Phenylalanine in the 508th position (P. F508del)
Hereditary Haemochromatosis (HH) is due to an excessive accumulation of dietary … and occurs due to a mutation in the … gene
Hereditary Haemochromatosis (HH) is due to an excessive accumulation of dietary IRON and occurs due to a mutation in the HFE gene
What is the most common mutation for Hereditary Haemochromatosis (HH)?
Missense mutation of Cysteine to Tyrosine at 282nd Position (P. C282Y)
What is the most common Autosomal Recessive Disorder in Northern Europe?
Hereditary Haemochromatosis (HH)
What does it mean that Hereditary Haemochromatosis (HH) is an example of Non-penetrance?
Non-Penetrance means that not all recessive individuals with the mutated C282Y allele (i.e. C282Y/C282Y), will display the HH phenotype and be affected with exogenous Iron accumulation.
What type of Disorder is Duchenne Muscular Dystrophy (DMD) and Becker Muscular Dystrophy (BMD)
Both DMD and BMD are examples of X Linked Recessive Disorders
Becker Muscular Dystrophy is (more/less) severe than Duchenne Muscular Dystrophy and stains Dystrophin in muscle biopsies (more/less) visible.
Becker Muscular Dystrophy is LESS severe than Duchenne Muscular Dystrophy and stains Dystrophin in muscle biopsies MORE visible.
What is the gene that is associated with both Duchenne Muscular Dystrophy (DMD) and Becker muscular Dystrophy (BMD)?
The Dystrophin gene= Encodes for the structural protein Dystrophin
What is the purpose of the protein Dystrophin?
Dystrophin (a structural protein) normally links the Cytoskeleton of Muscle cells to the Basement Membrane
What type of deletions occur to the Dystrophin gene for DMD and BMD, respectively?
DMD= Out of Frame Deletion (Why its more severe) BMD= In Frame Deletion (Why its less severe)
….. is an Autosomal Recessive Disorder of Amino Acid Metabolism as it affects the enzyme …… ……..
Phenylketonuria (PKU) is an Autosomal Recessive Disorder of Amino Acid Metabolism as it affects the enzyme Phenylalanine Hydroxylase
In PKU, what is the cause of the severe brain impairments associated with the disorder?
Excessive accumulation of Phenylalanine= Hyperphenylalaninemia
When should PKU be scanned and treated for?
Should be screened at birth and treated for immediately
What is the function of the enzyme Phenylalanine Hydroxylase?
Breakdown of Phenylalanine
What is the function of the enzyme Phenylalanine Hydroxylase?
Breaksdown Phenylalanine (F)
What are two clinical signs of Duchenne Muscular Dystrophy (DMD)?
1) Pseudohypertrophy of calves (Fat accumulation)
2) Gower’s Sign
3) Poor coordination (Tripping and Falling constantly)
What is a biomarker in the blood for Duchenne Muscular Dystrophy?
Excessive Creatine Kinase in the blood= Increases as Muscle dies and is degraded
What is a clinical biomarker in the blood for Duchenne Muscular Dystrophy?
Excessive Creatine Kinase (CK) in the blood= Increases as Muscle dies and is degraded
