Lecture 4: Genetic Mutations/Disorders

Question 1

Autosomal Mutations occur in … cells and are not …. , while Germline mutations occur in … cells and may be …

Answer 1

Autosomal Mutations occur in SOMATIC cells and are not INHERITED, while Germ-line mutations occur in GAMETIC cells and may be INHERITED

Question 2

When naming mutations/variants what is denoted as the +1 position?

Answer 2

The “A” of the Start Codon (AUG)

Question 3

Describe the Intron Mutation–> c89+21

Answer 3

c89 refers to the last exon nucleotide (Exon 89) and the mutation occurs 32 nucleotides into the Intron

Question 4

How would you write the Amino Acid mutation Tryptophan to Lysine at the 108th position (in AA single abbreviation)?

Answer 4

P. W108K

Question 5

What type of mutation is P. Asp47X

Answer 5

Missense Mutation (X refers to an improper STOP codon)

Question 6

What are the three STOP codons

Answer 6

1) UGA 2) UAA 3) UAG

Question 7

In a …. Insertion/Deletion the Open Reading Frame (ORF) is changed, whereas in a …. Insertion/Deletion the ORF is not changed

Answer 7

Frameshift; Non-Frameshift

Question 8

What is the single point mutation of Sickle Cell Anaemia?

Answer 8

P. G6V of the Beta-Subunit of Haemaglobin

Question 9

True or False: A Missense Mutation results from an early Stop Codon, while a Non-Sense Mutation results from a Substitution of different AAs.

Answer 9

False; A NON-SENSE Mutation results from an early Stop Codon, while a MISSENSE Mutation results from a substitution of different AAs.

Question 10

Define Non-Sense Mediated Decay

Answer 10

A Non-Sense mRNA mutation is recognized by a surveillance pathway within the cell and the Non-sense mRNA is degraded prior to translation.

Question 11

What two nucleotides does an Intron typically start and end with?

Answer 11

Introns typically start with “GU” and end in “AG”

Question 12

What mutations cause Neurofibromatosis Type 1 (NF1) and/or Menkes Disease?

Answer 12

Splice Site Mutations

Question 13

True or False: Splice Site Mutations lead to 1) New Splice Sites 2) Unmasking of Cryptic Splice Sites

Answer 13

True

Question 14

A missense mutation of the …. gene is responsible for Achondroplasia (i.e. “Dwarfism”).

Answer 14

FGFR gene on Chromosome 4 (c. 113 G > A)

Question 15

The FGFR gene is an example of a (Gain/Loss) of Function mutation as it (Over-inhibits/Under-inhibits) Cartilage formation, leading to Achondroplasia

Answer 15

Gain of Function Mutation; Over-inhibits Cartilage Formation

Question 16

True or False: An individual homozygous for the gene mutation of Achondroplasia is even shorter that an individual that is only heterozygous?

Answer 16

False; The homozygote form of Achondroplasia (both mutant FGFR gene copies) is lethal.

Question 17

What three organ systems does Marfan Syndrome affect?

Answer 17

1) Skeletal 2) Occular 3) Cardiovascular

Question 18

What is Pleitropy? What disease/syndrome is an example of Pleitropy?

Answer 18

One gene affects multiple organ systems in the body (Ex. Marfan Syndrome)

Question 19

What phenotype does someone with Marfan Syndrome have?

Answer 19

Extremely tall, potentially dislocated lens of the eye and aortic dissection

Question 20

The … gene on Chromosome 15 is responsible for Marfan Syndrome and is an example of a (Gain/Loss) of Function mutation.

Answer 20

The FB1N gene on Chromosome 15 is responsible for Marfan Syndrome and is an example of a LOSS of Function mutation.

Question 21

How does a mutation in FB1N lead to Marfan Syndrome?

Answer 21

• 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

Question 22

True or False: An increase in Maternal age leads to an increase in De Nova Mutations for Marfan Syndrome and Achondroplasia

Answer 22

False; An increase in PATERNAL age leads to an increase in De Nova Mutations for Marfan Syndrome and Achondroplasia

Question 23

True or False: The FB1N gene is a Loss of Function mutation and the FGFR gene is a Gain of Function mutation

Answer 23

True; FB1N mutation= Loss of Function= Marfan Syndrome

FGFR mutation= Gain of Function= Achondroplasia

Question 24

What are three clinical signs for diagnosis of Cystic Fibrosis (CF) in babies?

Answer 24

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)

Question 25

What is the gold-standard test to diagnose Cystic Fibrosis?

Answer 25

Sweat Test= Na+ and Cl- levels in the Sweat are way too High

Question 26

What is the mutated gene responsible for Cystic Fibrosis?

Answer 26

CTFR gene

Question 27

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

Answer 27

True

Question 28

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

Answer 28

False; In the Sweat Glands, CTFR encodes a normal ion channel that pumps Cl- ions and Na+ ions both INTO the cell

Question 29

What is the mechanism of disease for Cystic Fibrosis (CF) in Airway Epithelium when the CTFR gene is mutated?

Answer 29

• 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

Question 30

True or False: There is great variation in Clinical Symptoms/Severity of Cystic Fibrosis due to multiple CFTR mutations

Answer 30

True

Question 31

What is the major mutation associated with Cystic Fibrosis?

Answer 31

In-Frame deletion of Phenylalanine in the 508th position (P. F508del)

Question 32

Hereditary Haemochromatosis (HH) is due to an excessive accumulation of dietary … and occurs due to a mutation in the … gene

Answer 32

Hereditary Haemochromatosis (HH) is due to an excessive accumulation of dietary IRON and occurs due to a mutation in the HFE gene

Question 33

What is the most common mutation for Hereditary Haemochromatosis (HH)?

Answer 33

Missense mutation of Cysteine to Tyrosine at 282nd Position (P. C282Y)

Question 34

What is the most common Autosomal Recessive Disorder in Northern Europe?

Answer 34

Hereditary Haemochromatosis (HH)

Question 35

What does it mean that Hereditary Haemochromatosis (HH) is an example of Non-penetrance?

Answer 35

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.

Question 36

What type of Disorder is Duchenne Muscular Dystrophy (DMD) and Becker Muscular Dystrophy (BMD)

Answer 36

Both DMD and BMD are examples of X Linked Recessive Disorders

Question 37

Becker Muscular Dystrophy is (more/less) severe than Duchenne Muscular Dystrophy and stains Dystrophin in muscle biopsies (more/less) visible.

Answer 37

Becker Muscular Dystrophy is LESS severe than Duchenne Muscular Dystrophy and stains Dystrophin in muscle biopsies MORE visible.

Question 38

What is the gene that is associated with both Duchenne Muscular Dystrophy (DMD) and Becker muscular Dystrophy (BMD)?

Answer 38

The Dystrophin gene= Encodes for the structural protein Dystrophin

Question 39

What is the purpose of the protein Dystrophin?

Answer 39

Dystrophin (a structural protein) normally links the Cytoskeleton of Muscle cells to the Basement Membrane

Question 40

What type of deletions occur to the Dystrophin gene for DMD and BMD, respectively?

Answer 40

DMD= Out of Frame Deletion (Why its more severe)
BMD= In Frame Deletion (Why its less severe)

Question 41

….. is an Autosomal Recessive Disorder of Amino Acid Metabolism as it affects the enzyme …… ……..

Answer 41

Phenylketonuria (PKU) is an Autosomal Recessive Disorder of Amino Acid Metabolism as it affects the enzyme Phenylalanine Hydroxylase

Question 42

In PKU, what is the cause of the severe brain impairments associated with the disorder?

Answer 42

Excessive accumulation of Phenylalanine= Hyperphenylalaninemia

Question 43

When should PKU be scanned and treated for?

Answer 43

Should be screened at birth and treated for immediately

Question 44

What is the function of the enzyme Phenylalanine Hydroxylase?

Answer 44

Breakdown of Phenylalanine

Question 45

What is the function of the enzyme Phenylalanine Hydroxylase?

Answer 45

Breaksdown Phenylalanine (F)

Question 46

What are two clinical signs of Duchenne Muscular Dystrophy (DMD)?

Answer 46

1) Pseudohypertrophy of calves (Fat accumulation)
2) Gower’s Sign
3) Poor coordination (Tripping and Falling constantly)

Question 47

What is a biomarker in the blood for Duchenne Muscular Dystrophy?

Answer 47

Excessive Creatine Kinase in the blood= Increases as Muscle dies and is degraded

Question 48

What is a clinical biomarker in the blood for Duchenne Muscular Dystrophy?

Answer 48

Excessive Creatine Kinase (CK) in the blood= Increases as Muscle dies and is degraded