Genetics (Day 1)

Question 1

What are some causes of complete loss of function mutations (null mutations)?

Answer 1

• Nonsense
• Splice-site
• Frameshift
• Some missense and regulatory sites
• Large deletions or insertions

Question 2

What are some causes of partial loss of function mutations?

Answer 2

Most missense and some regulatory site

Question 3

What are the common mutations involved with DMD?

Answer 3

• Deletions
• Frameshift
• Nonsense

Question 4

What are the common mutations involved with BMD?

Answer 4

• In frame deletions

Question 5

What happens to the exon length in DMD?

Answer 5

It is NOT a multiple of 3, so there is a frameshift mutation (which leads to no protein due to premature termination codons).

Question 6

What happens to the exon length of BMD?

Answer 6

It IS a multiple of 3, so there is no frameshift mutation, which results in a protein with reduced function.

Question 7

Enzyme diseases are almost always ____?

Answer 7

Recessive

Question 8

What are the three clinical variant forms of PKU and what is their degree of severity?

Answer 8

1. Classical PKU (most severe)
2. Variant PKU (intermediate form)
3. Non-PKU Hyperphenylalaninemia (mildest form)

Question 9

What are normal plasma phenylalanine levels?

Answer 9

< 0.12 mM

Question 10

The enzyme phenylalanine hydroxylase (PAH) requires what cofactor for activity? What other enzymes require this cofactor?

Answer 10

• Tetrahydrobiopterin (BH4)

- Tyrosine Hydroxylase and Tryptophan Hydroxylase

Question 11

What are three mechanisms of dominance?

Answer 11

1. Haploinsufficiency
2. Gain of Function Mutations
3. Dominant Negative Mutations

Question 12

What are two explanations for variable expressivity?

Answer 12

1. Variation at other genes (effect of modifier genes)

2. Stochastic events in development (random chance)

Question 13

With NPS, where are the missense mutations clustered?

Answer 13

In the “LIM” and “HD” domains.

Question 14

What are some enzymes that when deficient, can cause hepatic porphyrias?

Answer 14

• Porphobilinogen demaminase
• Protoporphyrinogen oxidase
• Coproporphyrinogen oxidase
• Uroporphyrinogen decarboxylase

Question 15

What are some effects of a gain of function mutation?

Answer 15

• Increased gene function
• New gene function
• Mutant protein synthesis (usually missense, gene duplications, and chromosomal translocations)

Question 16

What kind of mutation is never present in gain of function mutations?

Answer 16

Null Mutations

Question 17

The mutant gene product interferes with the function of the normal gene product.

Answer 17

Dominant Negative Mutations

Question 18

What are some causes of Dominant Negative Mutations?

Answer 18

• Usually missense mutations

- NEVER null mutations

Question 19

Osteogenesis Imperfecta has clinical heterogeneity. Why is it’s null mutation unique?

Answer 19

The null mutation has a milder phenotype and missense mutations are more severe (opposite of most types of manifestations).

Question 20

What are common clinical manifestations of OI Type II?

Answer 20

• Perinatal Lethal
• Multiple in utero fractures
• Dominant negative glycine substitutions

Question 21

Explain the details of the mechanism of Osteogenesis Imperfecta.

Answer 21

In this disease, the glycine substitutions introduce bulkier amino acids that alter the helical structure of the alpha chain (thus altering the triple helix)

Question 22

This ⍺1-AT allele is associated with relatively mild disease. Homozygotes of this allele have 60% of their normal ⍺1-AT levels.

Answer 22

S (Slow) Allele

Question 23

This ⍺1-AT allele is associated with more severe disease, and 15% of people with this allele have normal ⍺1-AT levels.

Answer 23

Z (Very Slow) Allele

Question 24

This a1-AT allele is prone to aggregation and polymerization, associated with inclusions in hepatocytes, and increased inflammation in lungs following infection.

Answer 24

Z (Very Slow) Allele

Question 25

What disease has complete penetrance and variable expressivity?

Answer 25

Nail Patella Syndrome (NPS)

Question 26

What are the different mutations that can cause NPS?

Answer 26

Missense, Nonsense, Frameshift, and Splice Mutations

Question 27

What are the types of Gain of Function Mutations?

Answer 27

• Usually missense

- Gene duplications and chromosomal translocations

Question 28

For regulatory region mutations, mutations in the proximal promotor region are usually?

Answer 28

Null Mutations

Question 29

For regulatory region mutations, mutations in the enhancer region may?

Answer 29

Prevent transcription or change specificity

Question 30

What are the haplosufficiency (loss of function) diseases?

Answer 30

• Duchenne Muscular Dystrophy (DMD)
• Becker Muscular Dystrophy (BWD)
• Phenylketonuria (PKU)
• Tetrahydrobiopterin Deficiency (BH4)
• Oculocutaneous Albinism
• Maple Syrup Urine Disease

Question 31

What are the haploinsufficiency (loss of function) diseases?

Answer 31

• Nail Patella Syndrome (NPS)
• Cleidocranial Dystosis/Dysplasia
• Acute Hepatic Porphyria
• Acute Intermittent Porphyria (AIP)
• Variegate Porphyria (VP)

Question 32

What are the two dominant (gain of function) diseases?

Answer 32

• Thanatophoric Dysplasia (TD)

- Achondroplasia

Question 33

What is the dominant negative disease?

Answer 33

Osteogenesis Imperfecta (OI)

Question 34

What is the codominance disease?

Answer 34

Alpha 1-Antitrypsin Deficiency

Question 35

What are the regulatory site mutations?

Answer 35

• Polydactyly
• Campomelic Dysplasia
• Lactose Intolerance

Question 36

Explain the symptoms of WBS duplication.

Answer 36

• Short philtrum, thin lips
• Large teeth, arched palate
• Narrow forehead, normal periorbital area
• Severe language delay
• Relative spatial skills

Question 37

Explain the symptoms of WBS deletion.

Answer 37

• Long philtrum, full lips
• Small teeth, normal palate
• Broad forehead, full periorbital area
• Relative language
• Poor spatial skills