Single gene disorders Flashcards
Define single gene disorder
Any genetic disorders caused by a change affecting only one gene
What kind of genetic pattern do they tend to follow
Mandelian (AD, AR etc,)
What kind of single gene mutations are possible
Missense mutations
Nonsense mutations
Frame-shift mutations
What epigenetic mutations are possible
DNA methylation Chromatin modifications Deletions Insertions Inversions
How was the gene responsible for SCD seen for the first time in the 50s
Studying the protein and determining the amino acid change
What molecular biology methods can be used to identify single gene disorder
- Linkage analysis
- Positional cloning
Why are rare monogenic diseases difficult to detect by linkage analysis
Due to locus heterogeneity (mutations in
different genes resulting in the same clinical picture).
What is meant by X-linked recessive disorder?
Mostly male, born to carrier mothers
Half of the sons affected
Daughters of an affected fathers are carriers, never from father to son
Give 4 examples of X-linked recessive disorders?
1- Haemophilia A
2- X linked severe combined immune disorder
3- Duchenne muscular dystrophy
4- Becker muscular dystrophy
What is the role of dystrophin
Precise role unknown
- Appears to stabilise sacrolemma, protect muscle fibres from long term contraction- induced damage and necrosis
In Duchenne Muscular Dystrophy, what is wrong with the dystrophin gene
Absent or non funcctional due to a p21 mutation
When does DMD present? What is the life expectancy?
3-5 years
Mean life expectancy mid 20s
Does cardiomyopathy precede or follow skeletal progression in DMD
Follows
What is deficient in Haemophilia A
Clotting factor VIII
What is deficient in X linked SCID
Very few T cells and NK cells
What receptors are affected in SCID
IL2 and IL7 receptors
Give 3 examples of X-linked dominant disorders
- Some forms of retinitis pigmentosa
- Chondrodysplasia Punctat
- Hypophosphatemic rickets
Give 4 examples of autosomal recessive disorders
Phenylketonuria
Tay-Sachs
Haemochromatosis
Cystic Fibrosis
Give 4 examples of autosomal dominant disorders
- Huntington Disease
- Achondroplasia
- Polycystic kidney disease
- Werner mesomelic syndrome
What genetic change happens in Huntington disease
CAG expansion
What characterises Werner Mesomelic syndrome
Hypo/ aplasia of the tibiae
Preaxial polydactyly of the hands/ feet
Five fingers hand with absence of thumbs
What is meant by an Y-linked dominant disease
Only males affected, passes from father to son/ No generation skipped
Give an examplle of a Y lilnked dominant condition
Retinitis pigmentosa
Which is meant by genetic imprinting
Epigenetic phenomenon by which certain genes are expressed; imprinting silences the gene. If the father’s gene is imprinted only the mother’s is expressed
Give 3 examples of imprinting conditions
- Beckwith- Wiedemann Syndrome
- Prader- Willi Syndrome
- Angelman syndrome
What are the features of beckwiwth-wiedeman syndrome
Large size, predisposition to tumours
What are the features of Prader- Willi syndrome
Low muscle tone, cognitive probs
What is Angelman syndrome?
Neuro-genetic disorder characterised by severe intellectual and development disability, sleep disturbance and serizures
Name the genes involved in Angelman syndrome
HSA15
PWS
Describe how Angelman syndrome is inhertied
Both sexes affected
Only when a mutation chromosome is maternally inherited
If mother is carrier then chance of inheritance is 50%
Give 4 examples of mitochondrial conditions
Mitochondrial myopathy
Diabeties mellitus and deafness
Leber’s hereditary optic neuropathy
Leigh syndrome
What is gene therapy
Introduction of normal genes into cells in place of missing or defective ones in order to correct genetic disorders
When is gene therapy more possible
- Recessive
- Loss of function
- Tissue accessible
- Small gene
What are the 3 steps of dystrophin gene mutation
1- Disruption of the splicing acceptors to skip exon 45
2- Introduced of small indels to modulate the protein reading frame
3- Knockin of the missing exon 44 to resore full protein coding region
What technique could be used in the future to correct single gene disorders
CRISPR-Cas 9
