Lecture 22: X-linked disorders and Mitochondrial inheritance Flashcards
Overview X-linked recessive disorders;
- Males mostly affected
- All daughters of affected males are carriers
- No male to male transmission
- Carrier females have 50% chance transmitting trait to son and 50% giving carrier status to daughter
What are examples of X-linked recessive disorders?
Haemophilia
Fragile x syndrome
Duchennes muscular dystrophy
Give a brief overview of haemophilia and its clinical features
- Clotting disorder due to deficiency of either factor VIII or factor XI
- 1 in 5000 males
Clinical features
- Recurrent and spontaneous bleeds into joints, muscles, soft tissue
- Long term damage to affected joint
Give a brief overview of heamophilia management;
- Infusions of coagulation factor
- Pain relief
- Rest of affected joint
BUT - Risk of infection from blood products
- Time off
When it comes to genetic technology what can be analysed in heamophilia for management?
- Pedigree analysis
- Phenotype analysis
- DNA analysis
Direct mutations
Indirect analysis - Therapeutic stratagies
recombinant clotting factor
gene therapy
What is the function of pedigree analysis in heamophilia?
To determine which females are carries and which offspring / potential offspring are at risk
In a phenotype analysis of haemophilia why do female carriers have reduced clotting factor 8 levels?
May have lyonisation (one x is deactivated) therefore can present with some of the phenotype
What are the pitalls of a phenotypic study in heamophilia?
- Coagulation levels influenced by exercise, infection and oestrogens.
- Technical difficulties with fetal blood sampling
DNA analysis is more accurate, timely and definitive
What cells can be used for DNA analysis in haemophilia?
- Blood
- Skin, oral mucosae
- CVS
- Amniotic fluid cells
How can the DNA be analysed?
- Direct mutation analysis - Where the mutation responsible is known
- Indirect analysis i.e linkage or RFPL analysis where the mutation is not known
Is heamophilia caused by a single gene mutation?
No, haemophilia is a heterogenous disorder with several types of mutations i.e - Point mutations - Structural changes; Deletions Inversions
Whats the implication of genetic heterogeneity in heamophilia?
- Severity of condition (i.e the phenotype) may vary with different mutations
- For genetic diagnosis, need to know the mutation in each family
How can the genes be examined?
- Southern analysis looking for large structural changes i.e deletions
- Mutation scanning strategies i.e direct sequencing of the gene
- New mutation detected, needs to be confirmed to be pathogenic
i.e direct or indirect analysis
What is a direct mutation analysis approach?
Usually PCR based strategy
- Point mutation may result in gain or loss of a restriction enzyme site
- Allele-specific oligionucleotides
- Sequencing of PCR fragment
What is an indirect (linkage) analysis?
- Used where gene note cloned or pathogenic mutation unknown
- Uses linked markers i.e restriction fragment length polymorphism (RFLP) or microsatellite repeats to track the disease within a family
- Mostly PCR
What are the problems with indirect (linkage) analysis?
- Need to access several family members
- Need an informative marker gene
- Potential for recombination if marker gene distant from disease gene
- Non-paternity
What are the new therapeutic strategies for heamophilia?
- Recombinant factor 8 and 10 now available; potentially safer and free of infective risk.
10-20% factor 8 or 10 dramatically improves quality of life (down at 1% in some)
What is mitochondrial DNA?
- Double stranded circular DNA
- Maternally inherited
- 37 genes encode 13 proteins, distinct lack of non-coding intron sequences
- Mutation rate is 5-10x that of nuclear DNA
How does mtDNA become impacted by disease?
mtDNA mutations result in respiratory chain deficiency
- ATP
- Apoptosis
- ROS
- Cellular oxidation and reduction
What do mtDNA diseases generally result in?
Impacts high energy requiring organs i.e
- Brain
- Skeletal and heart muscle
