10. Human Genetics(2)

Question 1

What is an autosomal dominant disorder?

Answer 1

Autosomal dominant- where 1 copy of a mutation is sufficient for the individual to be affected

• Wild-type allele is recessive, and the defective allele is dominant
• More likely that one copy of the defective allele is present than two
• Inherited in a dominant pattern OR a new mutation arises in a single copy of the gene

Question 2

Describe the inheritance of an autosomal dominant disorder? (3)

Answer 2

• Phenotype appears in every generation
• Affected parent can transmit condition to any progeny according to Mendelian inheritance ratios
• Due to small progeny sample size in humans the typical ratios are not seen

(HTT) gene

Question 3

Describe Huntington’s disease?

Answer 3

• Huntington’s is a late onset autosomal dominant disorder
• Affects 1 in 10,000
• Is a progressive neurodegenerative brain disorder that causes-
• Neuronal death
• Cerebral atrophy
• Central nervous system disorder
• Uncontrolled movements
• Decrease in cognitive function
• Personality changes

Question 4

Describe the onset of Huntington’s disease?

Answer 4

Late onset

Question 5

What kind of diease is Huntington’s?

Answer 5

A polyglutamine repeat disease

Question 6

Why is Huntington’s a polyglutamine repeat disease?

Answer 6

HTT gene encodes a protein with a Poly Glutamine tract (encoded by CAG codon)

Normal copies of the gene have less than 36 repeats
More than 36 repeats cause Huntington’s disease

Question 7

What dictates the age of HD onset?

Answer 7

Number of glutamate repeats

Question 8

What does a mutate Huntington protein do?

Answer 8

The mutated HTT protein with poly Q expansion has a propensity to misfold and aggregate These protein aggregates form inclusion bodies in neurons
Numerous downstream effects

Question 9

How was the HTT gene identified?

Answer 9

Through positional cloning

Question 10

Describe autosmal recessive disorders? (3)

Answer 10

Autosomal recessive- 2 copies of a defective gene are required for an individual to
be affected

Wild-type allele is dominant, and the defective allele is recessive

Is inherited in a recessive pattern

Question 11

Describe the inheritance of autosomal recessive disorders?

Answer 11

Phenotype does not appear in every generation

Both parents must be carriers (but not affected by the condition)

transmit condition in accordance with Mendelian inheritance

Question 12

What is the most common severe autosomal recessive disorder?

Answer 12

Cystic fibrosis

Question 13

What gene is mutated in cystic fibrosis?

Answer 13

CFTR gene

Question 14

How was cause of cystic fibrosis found?

Answer 14

positional cloning

Question 15

What are symptomatic therapies for cystic fibrosis?

Answer 15

• Physiotherapy
• DNase to reduce mucus viscosity
• Antibiotics and Anti-inflammatories
• Mannitol spray to increase osmolality of mucus

Question 16

What does CFT stand for?

Answer 16

Cystic Fibrosis TRansmembrane conductance protein

Question 17

What does the CFTR gene do?

Answer 17

The CFTR protein transports Cl- ions across the plasma membrane of cells that line the lungs

CFTR protein ensures the hydration of the airways surface layer (ASL)

Question 18

What is the most common mutation for people who suffer from cystic fibrosis (CF)?

Answer 18

Delta f508 (70%) suffer from it

Question 19

What do different CFTR mutations result in?

Answer 19

Different molecular phenotypes

Question 20

How are different CFTR mutations treated with different drugs?(3)

Answer 20

Class III & IV mutations

• Potentiators (Ivacaftor)
• recovers the function of CFTR
• e.g., G551D and R117H

Class II mutations

• Correctors (Lumacaftor)
• Improve intracellular processing of CFTR
• e.g., DPhe508

Class I mutations

• Production correctors (Ataluren)
• Promote transcription of CFTR
• e.g., nonsense mutations

Question 21

How is cystic fibrosis treated depending on genetic profile?

Answer 21

Mutation specific targeted therapies- tailor treatment to an individual’s genetic profile

Cystic fibrosis sufferers can be homo/heterozygous for the CFTR mutations

Mutations do not always display one class of phenotype

Question 22

How are patients homozygous for the Phe508del mutation in CF treated?

Answer 22

• potentiator alone is not effective
• potentiator and a corrector (Orkambi) received FDA approval and is now
  available on NHS

Question 23

Describe x-linked disorders?

Answer 23

• X-linked disorders affect genes located on the X chromosome
• Most X-linked disorders are recessive
• Males can inherit the condition from the Female parent who is a carrier
• A female can inherit the phenotype only when both the Parents carry the allele
• Females are generally unaffected, but act as carriers

Question 24

Describe the inheritance of x-linked disorders?

Answer 24

Affected males

• Progeny never show disease phenotype
• All female progeny are carriers

Female carriers

• 50% chance of passing the disease phenotype onto their male progeny
• 50% chance of their female progeny being a carrier

Question 25

What is the most common X- linked recessive disorder?

Answer 25

Duchenne Muscular Dystrophy

Question 26

What is the onset disease and life expectancy for Duchene muscular dystrophy (DMD)?

Answer 26

• Disease onset is before 6 years of age

* Life expectancy is 20-30 years of age

Question 27

What does Duchene muscular dystrophy (DMD) do? (2)

Answer 27

(Multi-system disorder)

• Causes muscle weakness, wasting and
atrophy

• Skeletal muscle degeneration and cardiac myopathy

Question 28

Where is the gene responsible for Duchene muscular dystrophy (DMD) found?

Answer 28

X-chromosome

(Dystrophin protein) - 60% of cases

Question 29

What is the function of dystrophin protein?

Answer 29

In muscles, dystrophin is part of a protein complex that strengthens muscle fibres by linking a muscle cell’s cytoskeleton (actin) to the extracellular matrix (connective tissue)

(Dystrophin is located primarily in skeletal and in cardiac muscles)

Question 30

Describe the mutations in Duchenne muscular dystrophy (DMD)?

Answer 30

• Approximately 60% of DMD cases are due to deletions of at least one exon
• Deletion hotspot between exons 40-54

Question 31

What could Duchenne muscular dystrophy (DMD) be started with?

Answer 31

Anti-sense oligonucleotides

-Prevents recruitment of splicing machinery