Flashcards in Lecture 29 Deck (27)
What are four clinical features of Fragile X syndrome?
1) Physical features: long face, big ears, & hyperextensible joints
2) Moderate to severe retardation in males
3) Learning disabilities to mild retardation in females
4) X-linked dominant disorder with variable penetrance (Sherman paradox) and highly variable expressivity in females
What is unique about Fragile X syndrome in males with daughters?
Affected males with the X-linked dominant fragile X-syndrome have daughters who are never affected (non-penetrance because CGG repeats do not expand - we don't know why)
What happens in the FMR-1 gene in individuals affected with Fragile X syndrome?
In the 5' Untranslated region of the FMR-1 gene, there are 800-1000 SSR repeats of CGG. This causes:
1) Prevents transcription of gene (loss of function)
2) Chromatin remodeling (methylation of CG residues)
How many CGG repeats in the 5'-UTR of the FMR-1 gene are acceptable to have no loss of function?
What can be said about the CGG repeat in the FMR-1 gene in the general population?
FMR-1 CGG repeats are polymorphic
The ____ (larger/smaller) the premutation allele being passed to the next generation, the _____ (higher/lower) the ratio of full mutation in Fragile-X affected kids compared to just remaining as a premutation
Although premutation carrier males (between 50-100 repeats) never have affected daughters, can they have affected grandchilren?
Yes. Daughters are carriers and can pass on the mutation
Premutation carrier females are normal phenotype, but have increasing risk of full expansion affected children correlated with _____ of their allele (resolution of Sherman Paradox)
Summarize Fragile X syndrome in 3 points
1) have full expansion alleles (greater than 200 CGG repeats, typically 800-1000 CGG)
2) express no FMR-1 mRNA due to CpG hypermethylation in 5'UTR; FX is a loss of function disorder
3) affected females are heterozygotes and have a wide spectrum of disease symptoms (variable expressivity) due to random X inactivation
What is normal reduced penetrance?
80% of people in a pedigree who have a mutation show the mutation
20% of the people in a pedigree who have a mutation show the wildtype phenotype
What are the clinical features of Myotonic Dystrophy (DM)?
1) Normal Intelligence
2) Mild cases have cataracts and prefrontal baldness; no myotonia
3) Adult onset myotonia, muscular dystrophy and cardiac arrhythmia is common
4) Severe cases show congenital onset and rapid progression of muscular degeneration
5) Anticipation - unlike Fragile X, more severe symptoms and earlier onset in successive generations
What causes myotonic dystrophy?
1) The disease is due to CTG triplet expansion in the 3' UTR of DM-1 gene (DMPK) (85% of the time)
2) The disease can also be due to CCTG expansion in the UTR region of the DM-2 Zinc Finger 9 (ZNF9) gene
The two are indistinguishable by phenotype
What do the repeat sequences in DM1 cause associated to myotonic dystrophy?
Cataracts, Cardiac arrythmias, Gonadal failure, Hypo IgG, Myotonia, Muscular Dystrophy, Serological changes, & Insulin resistance
How many CTG repeats in the DM-1 gene causes phenotypic expression of the disease?
Over 40 CTG repeats in the 3' UTR of the DM-1 gene (DMPK) causes the expression of symptoms. Greater amount of CTG expansion causes more severe neuromuscular degneration and earlier age of onset
The defect found in the DM-1 gene causing DM is a _____ type of mutation
gain of function; results in a toxic mRNA, however the protein is made normally (it just has overexpression/gain of function)
What is anticipation of DM-1?
1) CTG expansions progress from generation to generation, making each generation worse off with a more severe expression of DM
2) Very large expansions result in congenital onset and early death
How is DM an example of locus heterogeneity?
Expansion of either the DM-1 (DMPK) or DM-2 (ZNF9) genes results in a gain of function toxic mRNA containing long tandem triplet repeats in 3' UTR of DM-1 or the first intron of DM-2
Sickle cell disease can be considered to be a ______ (gain/loss) of function
Gain of function; hemoglobin functions normally, but in the presence of low oxygen it polymerizes (this is considered to be a gain of function)
What is Huntington's disease?
Huntington's disease is an autosomal dominant disorder passed down through families in which nerve cells in certain parts of the brain waste away, or degenerate.
What does Huntington's disease result in?
1) Progressive chorea
4) Death, 10-15 after onset
What does the age of onset of Huntington's disease correlate with?
Highly variable age of onset correlates with number of tandem CAG triplet repeats in the coding region of the HD gene
What causes Huntington's Disease?
Disease due to expansion of CAG triplet repeat in the protein coding region of the gene: gain of function toxic protein has larger poly-glutamine tract
Is there anticipation associated with Huntington's disease?
Yes, but it does not affect the severity of the disease. It only affects the age of onset. Greater amount of tandem repeats = earlier onset
What is Kennedy disease?
1) Adult onset spinal bulbar muscular atrophy
2) Motor neuronopathy, but affected males can live long lives
What causes Kennedy disease?
Expansion of CAG triplet in coding region f Androgen Receptor (AR) gene causes gain of function of the androgen receptor
The Androgen receptor (AR) gene is an _____ gene that can undergo different mutations that result in ______
X-linked; gain or loss in function