Atypical Mandelian Inheritance Flashcards
What are the atypical mandelian inheritance?
- Genetic anticipation
- Pseudoautosomal inheritance
- Pseudodominant inheritance
- Mitochondrial inheritance
- Mosaicism
- Imprinting disorders
Define Genetic Anticipation
Tendency in certain genetic disorders for individuals in successive generations to present at an earlier age and / or with more severe manifestations
What is the common mechanism of Genetic Anticipation?
Expression of a trinucleotide repeat mutation.
Examples of disorder with Genetic Anticipation.
- Huntington’s disease
- Mytonic dystrophy
- Fragile X syndrome
Pathogenesis of Huntington’s disease?
Upstream (towards 5’ end of DNA) CAG repeats in Huntingtin Protein Gene in Chromosome 4 – CAG triplets increase – formation of polyGLUTAMINE chain – aggregation of polyglutamine chains – cell death in caudate and putamen
AUTOSOMAL DOMINANT INHERITANCE
Pathogenesis of Myotonic dystrophy
Downstream (Towards 3’ end of DNA) repeats of CTG – affect splicing of RNA
What is Pseudoautosomal Inheritance?
Close homology between X & Y chromosomes in the pseudoautosomal region (PAR) at the short arm tip of X Chromosome
Features of Pseudoautosomal Inheritance?
- Pseudoautosomal regions are not affected by X-inactivation
- Xpar and Ypar have genetic recombination
- There is Male to Male transmission
Example of Pseudoautosomal Inheritance?
Madelung’s deformity
- defective SHOX gene : Short stature HOmeoboX gene
growth disturbance in epiphyseal growth plate of distal radius – radius grows but curves towards palm – Ulna is pushed medially – prominent distal ulna
What is pseudodominant inheritance?
Autosomal recessive genes that behave like Autosomal Dominance due to increased carrier frequency.
- too many carriers
Example of Pseudodominant inheritance?
Gilbert syndrome
- intermittent unconjugated hyperbilirubinaemia
What is mitochondrial inheritance?
Inheritance of genetic material in the mitochondria of maternal origin
Distribution of mitochondria in gametes?
Female : in the secondary oocyte
Male : in the tail of the spearmatozoa – lost after penetration
Features of Mitochondrial DNA
- Small genome : 16.6kBases
- Double stranded circular DNA
- 37 genes
- No introns
- Heteroplasmy : heterogeneity in DNA composition because one mitochondrion has many copies of DNA
- No repair mechanism so high mutation rate
What are the common sites of manifestation of abnormal mitochondrial inheritance?
Organs with high energy demand: muscle, brain, eyes
How many base pairs does a human genome have?
3000 million base pairs
- 1.5% code for proteins
- remaining : Junk DNA – control promoters, enchancer sequence
Example of mitochondrial inheritance?
Leigh’s Disease
Mutation of mDNA MT-ATP 6 gene – defective ATP synthase – poor energy production in the motor area of the brain – progressive muscle weakness, respiratory & renal impairment, lactic acidosis, seizures, loss of motor skills
Compare and contrast mDNA and nuclear DNA.
- Location : mDNA - in mitochondrion; nDNA - in nucleus
- Source of DNA : mDNA - mother ; nDNA - both parents
- Number of bases : mDNA - 16.6kB ; nDNA - 300 million base pairs
- Introns : mDNA - no ; nDNA - yes
- Functions of DNA : mDNA - for mitochondrial enzymes mainly ; nDNA - for all proteins in the body
What is mosaicism?
New mutation acquired after fertilization.
Types of mosaicism
Somatic and Gonadal
Somatic - affects somatic and germ cells eg: McCune Albright Syndrome
Gonadal - affects germ cells - somatic cells are normal
What are imprinting disorders?
Expression of genes from just one allele because of modification to the DNA (epigenetics).
Modification of histones and the effects.
+ Acetyl - activation
+ Methylation - deactivation
+ Phosphate - apoptosis
Examples of imprinting disorders?
- Angelman syndrome
- NORMAL : activation of maternal copy of the gene
- ABNORMAL : deletion of maternal copy
~ learning difficulties - Prader Willi Syndrome
- NORMAL : paternal copy of the gene is active
- ABNORMAL : deletion of paternal copy
~ hypotonia, overeating, learning difficulties, hypogonadism
