10. Human Genetics(2) Flashcards
What is an autosomal dominant disorder?
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
Describe the inheritance of an autosomal dominant disorder? (3)
- 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
Describe Huntington’s disease?
- 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
Describe the onset of Huntington’s disease?
Late onset
What kind of diease is Huntington’s?
A polyglutamine repeat disease
Why is Huntington’s a polyglutamine repeat disease?
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
What dictates the age of HD onset?
Number of glutamate repeats
What does a mutate Huntington protein do?
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
How was the HTT gene identified?
Through positional cloning
Describe autosmal recessive disorders? (3)
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
Describe the inheritance of autosomal recessive disorders?
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
What is the most common severe autosomal recessive disorder?
Cystic fibrosis
What gene is mutated in cystic fibrosis?
CFTR gene
How was cause of cystic fibrosis found?
positional cloning
What are symptomatic therapies for cystic fibrosis?
- Physiotherapy
- DNase to reduce mucus viscosity
- Antibiotics and Anti-inflammatories
- Mannitol spray to increase osmolality of mucus
What does CFT stand for?
Cystic Fibrosis TRansmembrane conductance protein
What does the CFTR gene do?
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)
What is the most common mutation for people who suffer from cystic fibrosis (CF)?
Delta f508 (70%) suffer from it
What do different CFTR mutations result in?
Different molecular phenotypes
How are different CFTR mutations treated with different drugs?(3)
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
How is cystic fibrosis treated depending on genetic profile?
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
How are patients homozygous for the Phe508del mutation in CF treated?
- potentiator alone is not effective
- potentiator and a corrector (Orkambi) received FDA approval and is now
available on NHS
Describe x-linked disorders?
- 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
Describe the inheritance of x-linked disorders?
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
What is the most common X- linked recessive disorder?
Duchenne Muscular Dystrophy
What is the onset disease and life expectancy for Duchene muscular dystrophy (DMD)?
- Disease onset is before 6 years of age
* Life expectancy is 20-30 years of age
What does Duchene muscular dystrophy (DMD) do? (2)
(Multi-system disorder)
• Causes muscle weakness, wasting and
atrophy
• Skeletal muscle degeneration and cardiac myopathy
Where is the gene responsible for Duchene muscular dystrophy (DMD) found?
X-chromosome
(Dystrophin protein) - 60% of cases
What is the function of dystrophin protein?
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)
Describe the mutations in Duchenne muscular dystrophy (DMD)?
- Approximately 60% of DMD cases are due to deletions of at least one exon
- Deletion hotspot between exons 40-54
What could Duchenne muscular dystrophy (DMD) be started with?
Anti-sense oligonucleotides
-Prevents recruitment of splicing machinery
