LG 3.10 Genetics of Connective Tissue Disorders

Question 1

The specific location of a coding sequence on a chromosome is known as what?

Answer 1

Locus or loci (plural)

Question 2

When there is a mutation that affects a gene and results in an altered phenotype, what is the mutation affecting that leads to this change?

Answer 2

• Mutations lead to changes in transcription or translation, and eventually an abnormal (or no) protein product.
• These altered proteins is what results in the altered phenotype

Question 3

Do all mutations alter proteins?

Answer 3

• NO!
• Genes have sequences upstream or downstream that influence their activity (promoters, inducers, etc.)
• Mutations in these sequences can dramatically change the action of the gene.
• They can change how the gene is transcribed or translated.

Question 4

Do all mutations affect phenotypes?

Answer 4

• Not all.

- Some affect activity at the molecular level, but at the clinical level nothing is changed.

Question 5

What is wt? What does it refer to?

Answer 5

• Wildtype
• Most common normal type around.
• Possibly a mutated phenotype but still most common and therefore wt.
• No “normal” allele, most common allele!

Question 6

I am a carrier of Tay Sach’s but am totally normal, am I wt?

Answer 6

• Yes

- Wildtype is only based on phenotype

Question 7

What does haplosufficient and insufficient mean when referring to loss of function mutations?

Answer 7

• Haploinsufficient: one allele is wiped out and this results in disease, the other good allele (only one) is not good enough. Dominant mutation.
• Haplosufficient: the other allele is prominent enough to take over control and no change is made. Recessive mutation.

Question 8

What is a loss of function mutation? Is this a dominant or recessive change?

Answer 8

• Mutation that causes a protein to lose its function.

- Depends on haplosuffiency

Question 9

What is a gain of function mutation when referring to a protein? Are these recessive or dominant mutation?

Answer 9

• Take a protein and give it new function
• “x-man” or “spider-man” mutation
• Dominant mutation, give new function

Question 10

What is a dominant negative mutation?

Answer 10

• Abnormal function that interferes with the normal allele
• Sickle cell anemia: you have good hemoglobin and mutated hemoglobin, mutated hemoglobin interferes with the good and causes disfunction

Question 11

What is a transition or transversion mutation?

Answer 11

• 2 base pairs switch

- Doesn’t matter the difference between them, he didn’t care

Question 12

What is a missense mutation?

Answer 12

• Change one codon (base-pair) -> one amino acid change -> giant phenotype change
• Ex: sickle-cell

Question 13

What is occurring in a nonsense mutation?

Answer 13

• Codon changes to a stop codon.

- Stops the translation of the protein -> usually leads to a nonfunctional protein.

Question 14

What is a neutral mutation?

Answer 14

• Alters codons, alters amino acids
• Amino acids that change lead to no phenotypic change
• Neutral = no phenotypic change

Question 15

What happens in a silent mutation?

Answer 15

• Base-pairs change

- Due to wobble-base pairing => no change in amino acid

Question 16

What happens in a frameshift mutation?

Answer 16

• Add or subtract 1 base
• Add one = problem,, add two = problem,
  add three = NEW AMINO ACID!
• Protein becomes longer but no phenotypic change

Question 17

Patient with muscular dystrophy is producing a dystrophin gene product that is missing 35 amino acids on its carboxyl end. Which mutation is the best candidate?

A) neutral
B) missense
C) nonsense
D) frameshift
E) silent

Answer 17

• Nonsense

Question 18

Huntington’s disease is caused by a series of bases inserted into a gene. These are added in increments of 3, and add amino acids to the protein. The altered protein created is toxic to the cell. What best describes this type of mutation?

A) Loss of function
B) Gain of function
C) Dominant negative

Answer 18

• Gain of function mutation

Question 19

If there is a disease or phenotype that is caused by any one of a number of mutations of an allele or a locus, what is this an example of?

Answer 19

• Genetic heterogeneity

Question 20

What is the classic example of allelic heterogeneity?

Answer 20

• Cystic fibrosis, CFTR

- 2300 known mutant alleles for the CFTR gene that cause the disease phenotype

Question 21

Explain the difference between allelic and locus heterogeneity.

Answer 21

• Many different genes code for a certain phenotype, mutations that occur in any of these genes at different chromosomal loci (locus heterogeneity) can cause the same disease state or phenotype.
• If there is one gene coding the phenotype, but you can get many different types of mutations in the allele that lead to the disease state, this is allelic heterogeneity.

Question 22

Classic example of locus heterogeneity?

Answer 22

• Retinitis pigmentosa
• At least 35 loci mutations can create the phenotype
• These mutations can be both dominant and recessive

Question 23

I have blood type B+, and you probably do not. This is a good example of?

A) allelic heterogeneity
B) locus heterogeneity
C) penetrance
D) expressivity

Answer 23

• Both allelic heterogeneity and locus heterogeneity
• Many different alleles for AB or O
• Plus or minus is controlled by different genes

Question 24

What are some examples of stuff that is produced by fibroblasts?

Answer 24

• Collagen + elastin

Question 25

Is collagen only one type of protein? Where is it found in the body? What cells create collagen?

Answer 25

• Protein family, not one protein only
• Found in extracellular matrix
• Created by fibroblasts

Question 26

Regarding collagen genes are there many or few genes coding for collagen fibers? Are they located together on a chromosome? Are these genes large (lots of exons) or small?

Answer 26

• More than 34-45 genes coding for variations of collagen fibers
• Genes are spread on most chromosomes
• Significant number of exons

Question 27

Because collagen genes are so large, what are the pathological implications of multiple genes for collagen?

Answer 27

• Large genes, easily damaged by mutations

- Multiple genes therefore you can get damage and it won’t kill you because you have other genes

Question 28

What happens to the pre-pro-peptide of collagen once it enters the ER, what is needed to complete this task?

Answer 28

• Post translational modification
• Proline gets hydroxylated into hydroxyproline
• Asorbic acid (vitamin C) is needed for this to take place

Question 29

Would massive mutations in collagen genes that create disease states be inherited or de novo?

Answer 29

• Mostly de novo if causing a massive change.

- This is due to the fact that it would be far to difficult for these people to survive let alone bring a child to term.

Question 30

Ehlers-Danlos syndrome. What does it cause? How common? Type of mutation?

Answer 30

• Loose joints, stretchy skin
• Rare
• Recessive + dominant

Question 31

Epidermolysis Bullosa. What does it cause? How common? Type of mutation?

Answer 31

• Wounds on skin
• Rare
• New type

Question 32

Marfan Syndrome. Caused by mutations in what? What does it cause? How common? Type of mutation?

Answer 32

• Not collagen, fibrillin (part of elastin)
• Tall, skinny, lengthy digits etc.
• Rare
• Dominant

Question 33

Osteogenesis Imperfecta. Mutation in what? Causes what?

Answer 33

• Associated with Type 1 collagen mutation

- Weak bones