Mutations Flashcards
What is molecular pathology ?
Why a mutation result in a clinical phenotype
What are the types of mutations ?
- deletions
- insertions
- substitutions
What are the different types of substitutions ?
- missense = when an amino acid is replaced with a different amino acid
- nonsense = amino acid codon is replaced with a stop codon
What do deletion and insertion mutations cause ?
They can cause splice shifts which is where intron or exon splice sites are lost or created resulting in a frame shift mutation
What are the effects of mutations on humans ?
They can effect transcription or translation
What are the effects of the different types of mutations ?
- loss of function mutation
- gain of function mutation
- dominant negative mutation
- mutations that effect gene dosage
Describe loss of function mutation
- when a gene product has reduced or none of its normal function
- any mutation that inactivates gene product will result in clinical symptoms
- Duchenne muscular dystrophy is caused by loss of function mutation
Describe gain of function mutation
- gene product acquires a new abnormal function
- only the specific mutation that gives the product it’s new function will result in the clinical phenotype
- Huntington disease is caused by a gain of function mutation
Describe Huntingtons disease
- caused by a gain of function mutation
- the mutation occurs as the CAG triplet is expanded within the coding gene sequence for the protein huntingtin
- causes the death of medium spiny neurones in the striatum
- affected alleles have 36-100 CAG repeats
- strikes in midlife (30-50 years)
- motor, emotional and cognitive symptoms
- death within 15-20 years
- the greater the number of CAG repeats the earlier the age of onset
Describe dominant negative mutations
- when the mutant gene product not only loses its own function but also prevents other gene products from functioning correctly
- occurs where the mutation affects a multimeric protein encoded by more than 1 gene
- osteogenesis imperfecta is an example of a disease caused by a dominant negative mutation
Briefly describe osteogenesis imperfecta
- caused by a mutation in either COL1A1 or COL1A2 gene encoding type I collagen
- very mild OI occurs when the mutated gene product is excluded from type I collagen
- lethal OI occurs when the mutated gene product is incorporated into type I collagen
Describe mutations that effect gene dosage
- the mutation varies the level of gene product
- it is dependent upon gene and cell type
- Down syndrome is an example of a disease caused by mutations that effect gene dosage
Describe the characteristic features of Down syndrome
- occurs due to an extra but normal chromosome 21
- mental retardation
- characteristic faces
What is a locus ?
When individual genes or DNA have a chromosomal location that defines its position
What is an allele ?
An individual copy of a gene that is present at a locus on a single chromosome
- humans are diploid and therefore have two alleles for each chromosomal locus one inherited from the mother and the other from the father
What is a genotype ?
- combination of alleles that a person possesses at a locus
- homozygous = both alleles are the same
- heterozygous = alleles are different
What is meant by hemizygous ?
Males have only one allele for X and one allele for Y chromosomes and therefore are hemizygous
What is pedigree analysis ?
- representation of a family tree that uses standard symbols to depict biological characteristics
- it is used to understand how a particular mutation is inherited
What is a kindred ?
Extended families covering many generations are called kindreds
What is proband ?
The family member through which the family is first brought to the attention of clinicians is called the proband and may be marked with an arrow
What are the mandelian inheritance patterns ?
- autosomal dominant
- autosomal recessive
- X-linked dominant
- X-linked recessive
- Y-linked
What type of mutation causes DMD ?
Loss of function mutation
Briefly describe Duchenne muscular dystrophy
- progressive muscular weakness
- affects mostly males
- no treatment
- X-linked recessive disorder
What is Beckers muscular dystrophy ?
- much milder compared to DMD
- patients still walk at 60 years old
What is X-inactivation ?
It is a dosage compensation mechanism that ensures only one X chromosome is active in each cell
- occurs in all female mammals
Why do females with X:autosome translocation have DMD ?
- it would be expected that females with X:21 translocation would be carriers as DMD is recessive
- but X inactivation favours DMD
Describe the DMD gene
- it is the largest human gene at ~ 2.5 million base pairs
- locus is Xp21
- contains mostly introns and 86 exons
- the gene product is dystrophin
- mutations in dystrophin cause Duchenne and Beckers
Describe the mutations that cause DMD
- 60-65% of patients have deletions
- 5-15% of patients have duplications
- 20-35% of patients have small mutations, intron deletions or exon insertions of repetitive sequences
- frameshift mutations in dystrophin cause DMD
- frame neutral mutations cause BMD
What is the role of dystrophin ?
dystrophin maintains the strength, flexibility and stability of muscle fibres
What are the problems and solutions associated with gene therapy to combat DMD ?
Problems -
- very large mRNA
- muscle cells are post mitotic
- immune response
Solutions -
- use mini genes with crucial domains
- use adenoviral vectors
What is happloinsufficiency ?
A situation in diploid organisms when one copy of a gene is inactivated or deleted and the remaining functional copy of the gene is not sufficient to preserve normal function
What is a polymorphism ?
A DNA sequence variation that is common in the population
