Single Gene Disorders

Question 1

Explain the 2 general types of autosomal dominant disorders:

1. Loss of function mutations - defects in what 2 things
2. Gain of function mutations

Answer 1

1. Structural proteins and regulatory proteins

2. Normal protein with toxic properties

Question 2

1. 2 examples of loss of function autosomal dominant diseases - defect in regulatory proteins
2. 1 example of structural protein loss of function disease
3. 1 example of gain of function autosomal dominant diseases

Answer 2

1. Familial hypercholesterolemia and myotonic dystrophy
2. Osteogenesis imperfecta
3. Huntington disease

Question 3

Neurofibromatosis type 1

1. Type of disease
2. Gene defect?
3. Clinical presentation (4)
4. Important genetic concept related to this disease?

Answer 3

1. Autosomal dominant
2. Mutation in cell cycle regulatory protein
3. Cafe-au-lait spots, axillary freckling, neurofibromas, lisch nodules
4. Variable expression - some in same family mildly/severely affected

Question 4

Marfan syndrome:

1. Type of disease
2. Gene defect? What is the gene component of
3. Clinical picture?
4. Good example of pleiotropy - define

Answer 4

1. Autosomal dominant
2. Fibrillin gene - component of ECM and connective tissue
3. Skeletal abnormalities, hypermobile joints, myopia and detached lens, aortic aneurysm
4. Single mutation affects multiple organ systems

Question 5

Thalassemias

1. Type of disease
2. Gene defect?
3. Where in the world is it most frequent (3)
4. What is adult hemoglobin (HbA) composed of?
5. Humans have 2 copies of the beta globin gene on what chromosome? Alpha globin? How many copies of each?
6. How is fetal hemoglobin (HbF) different

Answer 5

1. Autosomal recessive
2. Imbalance in globin chain synthesis
3. Mediterranean sea, africa, and southeast asia
4. 2 alpha and 2 beta chains
5. Single gene on chromosome 11 for beta (so 2 copies total). 2 genes on chromosome 16 for alpha (so 4 copies total)
6. Gamma chains replace beta chains

Question 6

Explain each of the following types of thalassemia
1. Alpha? What accumulates?

2. Beta? What accumulates?

Answer 6

1. Results from insufficient synthesis of the alpha chain- beta chain accumulates
2. Results from insufficient synthesis of the beta chain - alpha chain accumulates

Question 7

Beta thalassemia:

1. Alpha chain accumulates - are they soluble or insoluble?
2. Fate of cells?
3. Results in what condition
4. How will lab results look?

Answer 7

1. Very insoluble
2. Premature death of cells
3. Hemolytic anemia
4. Low hemoglobin and excess alpha globin

Question 8

1. Beta thalassemia minor vs major
2. What is B+? What is B0?
3. What is thalassemia intermedia

Answer 8

1. Minor= 1 normal and 1 mutant
   Major= 2 mutant copies
2. B+= leads to reduced amounts
   B0= leads to total absence of functional B-globin
3. B+/B+ or B0/B+

Question 9

1. Thalassemia minor may be mistaken for?

2. How is it diagnosed? (2)

Answer 9

1. Iron-deficiency anemia

2. Hemoglobin electrophoresis or blood work

Question 10

1. Why do babies born with thalassemia major appear normal at first?
2. How will these patients present? (4)

Answer 10

1. Because babies have HbF, become anemic when B globin synthesis increases to get HbA
2. Severe anemia, hepatosplenomegaly, skeletal deformities, systemic iron overload

Question 11

Thalassemia major:

1. What type of skeletal deformities will they show? Why?
2. Systemic iron overload is due to what 3 things?
3. Treatment for this condition

Answer 11

1. Face/skull; due to bone marrow expansion (to increase RBC production)
2. RBC turnover, increased iron absorption in diet, accumulation in liver and heart
3. Regular blood transfusions with iron chelation therapy, bone marrow transplant (dangerous), potential gene therapy

Question 12

Thalassemia intermedia:

1. Varies in severity, treatment?

Answer 12

1. Blood transfusions are only required occasionally

Question 13

Alpha thalassemia:

1. What is the most frequent mutation?
2. Normal genotype would be?
3. Silent carrier?
4. Alpha thalassemia trait
5. HbH disease - clinically severe
6. Hydrops fetalis - usually fatal at birth

Answer 13

1. Deletion of the entire gene
2. aa/aa
3. -a/aa
4. —/aa and -a/-a
5. —/-a
6. —/—

Question 14

1. Symptoms of silent carriers?
2. Symptoms of a-thalassemia trait
3. Symptoms of HbH disease
4. If all 4 alpha genes are missing, what happens?

Answer 14

1. Essentially normal - no RBC abnormality
2. Same as those with beta thalassemia minor
3. Same as those with beta thalassemia intermedia
4. Usually lethal in utero or shortly after birth

Question 15

What does the gamma globin form in cases of alpha thalassemia in utero/shortly after birth

Answer 15

Hemoglobin bart (Hb Bart)

Question 16

Alpha thalassemia:

In patients with at least one copy of the alpha globin gene (surviving patients), what accumulates?

Answer 16

HbH

Question 17

Compare HbH and Hb Bart to the aggregates seen in beta thalassemia

Answer 17

The ones in alpha thalassemia (HbH and Hb Bart) are more soluble and less toxic; less severe phenotype

Question 18

How often do the following need blood transfusions:

1. Thalassemia major
2. Thalassemia intermedia

Answer 18

1. Once every 2-4 weeks

2. Only when needed (like during an infection)

Question 19

Males are considered __ when thjey have genes on the X chromosome, why?

Are phenotype issues more common in males or females for X linked diseases, why

Answer 19

Hemizygous; only have one X chromosome

Males because they only need 1 copy of a defective X to be phenotypic, females need 2

Question 20

Hemophilia A and B

1. Type of disease
2. Gene defect for both
3. 3 mutation types that can contribute to the disease
4. Wide range of clinical severity based upon?
5. How can you tell A and B apart

Answer 20

1. X linked
2. A= blood clotting factor VIII; B=blood clotting factor IX
3. Deletions, nonsense mutations, DNA inversions
4. Clotting factors level of activity
5. Clinically the same, need further testing to determine which one

Question 21

1. Which is more common? In males or females?

2. Clinical presentation

Answer 21

1. A - males

2. Prolonged bleeding episodes, intracranial hemorrhage, easy bruising, hemarthrosis

Question 22

1. What is hemarthrosis
2. Most frequent cause of death for hemophiliacs ?
3. Treatment

Answer 22

1. Bleeding into joints/loss of joint mobility
2. AIDs
3. Factor replacement therapy (via infusion)

Question 23

Duchenne and Becker Muscular dystrophy (DMD and BMD):

1. Type of disease
2. Gene defect in both
3. Describe this gene
4. Size of this gene, why it is significant

Answer 23

1. X linked
2. Dystrophin for both
3. Protein involved in cytoskeleton of muscle and brain cells
4. Huge - thought to be the reason why mutations occur more frequently compared to some other genes

Question 24

1. DMD-what type of mutation
2. BMD-what type of mutation? How does it present
3. Which is more common?

Answer 24

1. Insertions/deletions causing frameshifts (not a factor of 3)
2. Insertions/deletions that are a factor of 3 - results in partially functional dystrophin protein and milder symptoms
3. DMD

Question 25

1. DMD - clinical presentation? When does it become apparent? Age of death? 2. BMD - clinical presentation? When does it become apparent? Age of death? 3. Treatment

Answer 25

1. Progressive muscle wasting/cognitive impairment. Wheel chair bound. Age 5. Early 20s from respiratory/cardiac insufficiency 2. Similar symptoms but less severe. Apparent at 11. Death ~42 3. No curative treatment, therapeutic only

Question 26

Fragile X syndrome: 1. Type of disease 2. Cause? 3. Clinical presentation 4. Most common INHERITED cause of ? 5. Most common known cause of?

Answer 26

1. X linked 2. Trinucleotide repeat expansion (FMR1), 5’ non-coding region 3. Long face, large ears and mandible, macro-orchidism (large testes) 4. Mental impairment 5. Autism

Question 27

1. Fragile X syndrome appears in some females due to ? 2. How will an inactive X chromosome look under EM? 3. Altered chromatin structure is associated with 4. X inactivation is fixed and incomplete - what does that mean

Answer 27

1. Lyonization (X inactivation) of a percentage of the normal X chromosome 2. Highly condensed Barr body in the nuclei 3. Highly methylated DNA 4. Fixed= all cells that descend from the inactivated X will also have an inactivated X; incomplete= some genes remain available for transcription

Question 28

Color blindness is what type of disease?

Answer 28

X linked

Question 29

Name 2 single gene disorders that do not manifest until later in life Onset?

Answer 29

Huntington disease and myotonic dystrophy ~30-40s

Question 30

Locus heterogeneity: 1. Define 2. Example of a disease 3. Can display several different?

Answer 30

1. When the same disease phenotype can be caused by mutations in different genes 2. Ehlers-danlos syndrome (EDS) 3. Inheritance patterns (autosomal dominant, recessive or X linked)

Question 31

Name the mutation in the following: 1. EDS autosomal dominant 2. EDS autosomal recessive 3. EDS X linked

Answer 31

1. Collagen genes 2. Lysyl hydroxylase 3. Copper binding protein (gene located on X chromosome)

Question 32

EDS X linked 1. Mutation in copper binding protein leads to? 2. What is copper essential for?

Answer 32

1. Reduced copper availability in the serum | 2. Activity of lysyl oxidase (cross linking of collagen fibers)

Question 33

30% of cases of DMD (X linked) result from? From which parent?

Answer 33

New mutations inherited from the mother

Question 34

Anticipation 1. Define 2. Most associated with diseases caused by? 3. 3 examples of these type of diseases 4. Severity of disease is directly correlated to?

Answer 34

1. Most recent generation of affected individuals show an earlier onset and/or more severe symptoms than the previous generations 2. Trinucleotide repeat expansions 3. Fragile X, myotonic dystrophy, and Huntington 4. Length of the segment containing repeats

Question 35

Hardy-Weinberg 1. 2 assumptions? 2. Relationship between? 3. Allows us to determine?

Answer 35

1. Population is large and individuals mate at random with respect to their genotypes at a given locus 2. Genotype frequencies and gene frequencies 3. Genotype frequencies if we know the gene frequencies and vice versa

Question 36

1. What is the primary source of all new genetic variation in populations 2. Do these rates differ much from population to population

Answer 36

1. Mutations | 2. No

Question 37

1. Natural selection influences ___, how? 2. What helps explain why most genetic diseases are relatively rare? 3. Which has lower gene frequencies: diseases that require only a single copy of a mutant gene or diseases that can remain hidden in heterozygotes?

Answer 37

1. Gene frequencies by selecting for genes that promote survival/fertility (fitness) 2. Reduced fitness of disease genes 3. Diseases that require a single copy of a mutant gene have lower gene frequencies

Question 38

Name a recessive gene (disease) that has a very high rate

Answer 38

Sickle cell anemia

Question 39

1. Heterozygotes for thalassemia mutations have some protection against? 2. Heterozygotes for cystic fibrosis mutation are protected against?

Answer 39

1. Malaria | 2. Typhoid fever

Question 40

Genetic drift 1. Occurs in what kind of populations 2. Another name? 3. More cases of what disease are seen in old order amish?

Answer 40

1. Populations with finite sizes (small) 2. Founder effect 3. Ellis van creveld disease

Question 41

Ellis van Creveld disease 1. Type of disease 2. Gene mutation 3. Symptoms

Answer 41

1. Very rare autosomal recessive 2. EVC gene 3. Polydactyly and short limbed dwarfism

Question 42

Gene flow: 1. Results from 2. Why is gene flow being seen more frequently ?

Answer 42

1. Exchange of genes among populations | 2. Many parts of the world are becoming less isolated - breeding between different populations