Highlight some differences between monogenic diseases and complex disorders.
Monogenic
- Clear inheritance
- No environmental influence
- Rare
- eg Huntington Disease, CF, Haemophilia
Complex Disorders
- No clear inheritance
- Environment essential
- Common
- e.g. Type 2 Diabetes, Schizophrenia, Crohn’s disease
What is mendelian inheritance?
Process whereby individuals inherit and transmit 1 out of 2 alleles present in homologous chromosomes to their offspring
What is an allele?
Alternate form of a gene/DNA sequence AT THE SAME LOCUS
Different alleles may be described as ………… or ………..
Mutations or polymorphisms
What is the difference between mutation and polymorphism?
Mutation - any heritable change in DNA sequence
Polymorphism - mutation that >1% frequency in a given population
POLYMORPHISMS are still usually called mutations if they contribute to monogenic disease.
Polymorphisms may contribute to complex diseases
Missense mutation vs Nonsense mutation?
THESE ARE BOTH POINT MUTATIONS
Missense - codon changes for different aa
Nonsense - codon changes for a stop codon. Polypeptide chain ends prematurely
What are the 5 types of Mendelian Inheritance patterns?
- Autosomal dominant
- Autosomal recessive
- X-linked dominant
- X-linked recessive
- Mitochondria
X linked dominant is rare
Describe autosomal dominant.
- At least one parent is affected
2. 50% risk of each child being affected
Huntingtons disease?
- It is autosomal dominant.
- Motor, cognitive and psychiatric dysfunction
- Onset 35-44 years
- Survival is 15-18 years after onset
MECHANISM:
- HTT gene on Chr 4 encodes Huntingtin
- HD patients inherit one mutated copy of HTT gene
- Mutated gene encodes toxic form of protein - forms “clumps”
- Causes cell death in basal ganglia giving rise to symptoms.
What are the patterns of inheritance with Huntingtons? (GENETIC ANTICIPATION)
- Age of onset decreases as you go down the family tree
2. Severity increases
What is the molecular basis for Huntingtons?
Unstable CAG triplet repeat
Number of repeats may increase with each generation
More repeats = more likely to be affected
Describe Autosomal recessive.
- No affected parent
- Usually no family history
- 25% risk of child being infected, 50% risk of child being a carrier
Describe CF.
- Cystic Fibrosis is an autosomal recessive condition
- Thick mucus in lungs causes breathing problems
- Blockages in pancreas may affect digestive enzymes
MECHANISM:
- CFTR gene encodes CFTR protein (CF transmembrane conductance regulator)
- CF patients inherit 2 copies of a mutated form of CFTR gene
- No functional CFTR protein means Cl- channels affected in epithelial cells.
- Salt/water regulation disrupted, which causes thick mucus
What is the molecular basis for CF?
Many different mutations identified (>!500)
Most common is delta F508.
Deletion affects folding of CFTR protein
What else can mutations in the CFTR gene do?
It can cause infertility, due to Congenital Absence of the Vas Deferens (CAVD), causing azoospermia.
Describe X linked recessive conditions.
- No affected parents
- Only males usually affected
- Transmitted by female carrier
- Sons have a 50% chance of infection
- Daughters have 50% chance of carrying
Describe haemophilia.
- X linked disease.
- Blood clotting disorder
- There are 2 types: A and B
- Treated successfully with injections of clotting factor
MECHANISM:
- Haemophilia A is caused by boys inheriting one mutated copy of the F8 gene.
- The F8 gene on Chr X encodes coagulation factor 8.
- Haemophilia B is caused by F9 mutation (Chr X).
- F9 codes for coagulation factor 9.
- Identical symptoms to Haemophilia A, but haemophilia B is much rarer.
Give an example of same gene, different disease.
CFTR - cystic fibrosis (delta F508) or vas deferens
Give an example of same disease, different genes.
Haemophilia A and B.
Give an example of same disease, different genes and different inheritance pattens.
Different forms of epidermolysis bullosa can be autosomal dominant or autosomal recessive.
What is meant by incomplete penetrance?
Symptoms not always present with people who have disease causing mutation
What is meant by variable expressivity?
Disease severity may vary between individuals with same disease causing mutation
Both incomplete penetrance and variable expressivity are features of ………. inheritance.
Dominant
What is phenocopy?
Having the same disease with different underlying causes
Epistasis?
Interactions between the disease gene mutation and other modifier genes can affect the phenotype.
What are the general molecular mechanisms of Dominant conditions?
They’re usually gene mutations coding for toxic proteins.
Mutated gene effects mask the normal gene
What are the general molecular mechanisms of recessive conditions?
They’re usually caused by the absence of a functional protein.
Effects of mutated gene only seen because normal gene absent
What is the mechanism of codominant conditions.
Effects of both the normal and mutated genes are present (e.g. sickle cell)
How do you treat dominant//codominant conditions?
NEUTRALISE effects of toxic protein or SWITCH OFF mutant gene to unmask normal gene
How do you treat recessive conditions?
RESTORE activity of missing protein - either replace the gene or the protein product or the affected tissues