Unusual Methods of Inheritance Flashcards
1
Q
What is genetic anticipation and give an example.
A
- Genetic disease with worsening severity and earlier onset as passed down generations
- EXAMPLE: Myotonic dystrophy - autosomal dominant - causing progressive muscle deterioration and myotonia
2
Q
Why does myotonic dystrophy show genetic anticipation? PART 1
A
- Usually individuals have an expanding CTG trinucleotide which repeats 5-37 times
- In MD, unstable CTG repeats in regulatory region of DMPK gene which increase with successive generations
3
Q
Why does myotonic dystrophy show genetic anticipation? PART 2
A
- Increase in repeats = greater severity
- Affects regulation of DMPK gene (alters RNA processing and interferes with protein production)
4
Q
What is fragile X syndrome?
A
- X-linked dominant disease - more common in males than females
- Cause long faces and large ears
- Frequent single genetic cause of autistic spectrum disorder
5
Q
How does Fragile X syndrome occur? PART 1
A
- Diseasing causing gene is FMR1 gene on X chromosome, encodes FMRP protein which plays role in brain/synaptic development
- Unstable CGG trinucleotide repeats
- 50-200 copies won’t cause syndrome but causes associated disorder
- 200+ copies causes syndrome
6
Q
How does Fragile X syndrome occur? PART 2
A
- Expansion occurs when females with unstable associated condition pass on diseased genes
- Males with associated condition don’t have affected daughters.
- Daughters with associated condition likely to have affected offspring.
7
Q
What is DNA methylation and how does it influence Fragile X syndrome? PART 1
A
- Attachment of methyl groups to 5’ regions of gene
- Added to cytosine group, catalysed by DNA methyltransferase
8
Q
What is DNA methylation and how does it influence Fragile X syndrome? PART 2
A
- Increases with increased repeats at promoter which reduces binding of transcription factors and gene expression
- In Fragile X syndrome, methylated trinucleotide repeats at 5’ UTR (promoter) region of FMR1 gene
9
Q
Describe genomic imprinting.
A
- For some genes, only one active allele. One of inherited alleles from parents is transcriptionally silenced i.e imprinted
- Inactivated by methylation
- IMPRINTING - process of gene silencing
10
Q
Describe Prader-Will syndrome (PWS)
A
- Deletion of base pairs from long arm of chromosome 15 (C15)
- Occurs when C15 deletion inherited from father
- CLINICAL PRESENTATION: Short stature, obesity, small hands and feet
- Can also occur when deletion inherited from father, and remaining copy contains maternally imprinted alleles
11
Q
Describe Angelman Syndrome (AS)
A
- Deletion of base pairs from long arm of chromosome 15 (C15)
- Occurs when C15 deletion inherited from mother
- CLINICAL FEATURES: Seizures and severe intellectual disability
- Can also occur when deletion inherited from mother, and remaining copy contains paternally imprinted alleles
12
Q
What is uniparental disomy and how can it cause PWS and AS?
A
- Both copies of chromosome inherited from one parent
- PWS = When 2 maternal copies of C15 inherited, no paternal copies
- Other way round for AS
13
Q
Describe mitochondrial inheritance and mutations.
A
- Mutations occur in mtDNA - double stranded circular molecules
- Maternal inheritance
- mtDNA encodes proteins involved in oxidative phosphorylation
14
Q
Why is there a high mtDNA mutation rate?
A
- Lack of DNA repair mechanisms
- Damage from free oxygen radicals produced during oxidative phosphorylation
15
Q
Describe heteroplasmy.
A
- Each cell contains population of mtDNA molecules - some mitochondria are mutated and some are not
- mtDNA replicates during cell division and mitochondria sorted randomly amongst daughter cells
- Varibale expression of mitochondrial disease due to random distribution of mutated and non-mutated mitochondria
