Lecture 14 - Single gene disorders

Question 1

What are 2 autosomal diseases (single gene disorders)?

Answer 1

• Huntington’s disease (autosomal dominant)
• Cystic Fibrosis (autosomal recessive)

Question 2

What is an X-chromosome linked disease?

Answer 2

• Duschenes Muscular Dystrophy

Question 3

How many people have a single gene disorder?

Answer 3

1 in 17 people

Question 4

What is an autosomal dominant disorder?

Answer 4

• where 1 copy of a mutation is sufficient for the individual to be affected
• Wild-type allele is recessive, and the defective 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
• phenotype appears in every generation
• affected parent can transmit condition to any progeny according to Mendelian inheritance ratios
• due to small progeny sample sizes in humans the typical ratios are not seen

Question 5

What is Huntington’s disease?

Answer 5

Huntington’s is a late onset autosomal dominant disorder
- affects 1 in 1000
is a progressive neurodegenerative brain disorder than causes:
- neuronal death
- cerebral atrophy
- central nervous system disorder
- uncontrolled movements
- decrease in cognitive function
- personality changes

• affects every generation
• genomic region responsible for the disease was first mapped in 1983 through positional cloning
• the HTT gene was identified and cloned a decade later (pre-genomic era)

Question 6

What does it mean that Huntington’s disease is 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

How does the number of glutamate repeats dictates the age of Huntington’s disease onset?

Answer 7

• the greater the number of CAG repeats the earlier the onset of disease
• Huntington’s disease shows incomplete penetrance
• CAG repeats are unstable and are prone to expansion
• CAG repeats can expand upon parental transmission

The signs and symptoms appear at an earlier age as Huntington’s disease is passed on from one generation to the next (anticipation)

Question 8

How does mutated Huntington protein aggregate?

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

What are the downstream effects of HTT Aggregation?

Answer 9

• Protein sequestration (dysregulation of transcription)
• impairs axonal transport
• mitochondria dysfunction

Question 10

What is a summary of Huntington’s disease?

Answer 10

• an autosomal dominant neurodegenerative condition
• HTT gene was identified through positional cloning
• is a polyglutamine expansion disorder
• number of repeats correlates with the age of onset

Question 11

What is an autosomal recessive disorder?

Answer 11

2 copies of a defective gene are required for an individual to the affected
- wild-type is dominant, and the defective allele is recessive
- is inherited in a recessive pattern

Question 12

Does the phenotype of an autosomal recessive disorder appear in every generation?

Answer 12

no
- both parents must be carriers (but not affected by the condition)
- transmit condition in accordance with Mendelian inheritance

Question 13

What is cystic fibrosis?

Answer 13

• cystic fibrosis is the most common severe autosomal recessive disorder
• approximately 1 in 2000 affected and 1 in 22 are carriers
• characterised Hh the build-up of thick mucus that can damage many of the body’s organs
• the CFTR gene and mutations responsible for causing cystic fibrosis was identified by positional cloning (like Huntington’s disease)

Question 14

What are symptomatic therapies?

Answer 14

• physiotherapy
• DNase to reduce mucus viscosity
• Antibiotics & anti-inflammatories
• Mannitol spray to increase osmolality of mucus

Question 15

Describe how Cystic fibrosis is caused by mutations in CFTR gene?

Answer 15

• The CFTR gene encodes the Cystic FIbrosis TRansmembrane conductance protein
• 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 16

What are mutations in cystic fibrosis?

Answer 16

• mutations are found throughout the CFTR gene and include mis-sense, non-sense and frame-shift mutations
• 70% of CF sufferers carry delta F508 mutation
• 15 further mutations accounts for 50% of the remaining cases
• additional mutations are “private mutations”

Question 17

What are the different molecular phenotypes that result from different CFTR mutations?

Answer 17

• no protein
• no traffic
• no function
• less function
• less protein
• less stable

treatment of cystic fibrosis will depend in the nature of the mutation and resulting phenotype

Question 18

Are different CFTR mutations treated with different drugs?

Answer 18

YES

Question 19

Describe the treatment of cystic fibrosis

Answer 19

• mutation specific targeted therapies - tailor treatment to an individual’s genetic profile
• cystic fibrosis sufferers can be homo/heterozygous for the CFTR mutations
• mutations don’t always display one class of phenotype
• patients homozygous for the Phe508del mutation
• potentiator alone is not effective
• potentiator and a corrector (Orkambi) received FDA approval and is now available on NHS

Question 20

How can the nature of CFTR mutations affect access to drug?

Answer 20

• often medications for rare conditions are expensive
• Orkambi treatment costs £100K/year

Question 21

What is a summary of cystic fibrosis?

Answer 21

• it is an autosomal recessive disorder
• mutations are found throughout the CFTR gene
• depending on the nature of the mutation, treatments are being developed that directly target specific genetic variants

Question 22

What are X-linked disorders?

Answer 22

• 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, for serious conditions, but a few as carriers

Question 23

What is Duchenne Muscular Dystrophy (DMD)?

Answer 23

• Duchenne Muscular Dystrophy is the most common X-linked recessive disorder
• Disease onset is before 6 years of age
• Life expectancy is 20-30 years of age
• Due to the age of onset, is exclusively passed on by the mother

Question 24

How does Duchenne Muscular Dystrophy (DMD) manifest?

Answer 24

• multi-system disorder
• causes muscle weakness, wasting & atrophy
• skeletal muscle degeneration and cardiac myopathy

Question 25

How big is Duchenne Muscular Dystrophy?

Answer 25

• largest known human gene (2.4Mb) containing 79 exome and encodes the Dystrophin Protein 427kDa

Question 26

What is the function of Dystrophin protein?

Answer 26

• dystrophin is located primarily in skeletal and in cardiac muscles
• 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).

Question 27

What are mutations in Duchenne Muscular Dystrophy (DMD)?

Answer 27

• approx. 60% of DMD cases are due to deletions of at least one exon]- deletion hotspot between exons 40-54
• deletions can cause frame-shifts
• Becker’s Dystrophy is also caused by mutation in Dystrophin gene

Question 28

What is the treatment of DMD?

Answer 28

with anti-sense oligonucleotides - (Eteplirsen) has received accelerated approval from the US FDA