Lecture 29

Question 1

What are four clinical features of Fragile X syndrome?

Answer 1

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

Question 2

What is unique about Fragile X syndrome in males with daughters?

Answer 2

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)

Question 3

What happens in the FMR-1 gene in individuals affected with Fragile X syndrome?

Answer 3

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)

Question 4

How many CGG repeats in the 5’-UTR of the FMR-1 gene are acceptable to have no loss of function?

Answer 4

<=50

Question 5

What can be said about the CGG repeat in the FMR-1 gene in the general population?

Answer 5

FMR-1 CGG repeats are polymorphic

Question 6

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

Answer 6

larger; higher

Question 7

Although premutation carrier males (between 50-100 repeats) never have affected daughters, can they have affected grandchilren?

Answer 7

Yes. Daughters are carriers and can pass on the mutation

Question 8

Premutation carrier females are normal phenotype, but have increasing risk of full expansion affected children correlated with _____ of their allele (resolution of Sherman Paradox)

Answer 8

Size

Question 9

Summarize Fragile X syndrome in 3 points

Answer 9

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

Question 10

What is normal reduced penetrance?

Answer 10

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

Question 11

What are the clinical features of Myotonic Dystrophy (DM)?

Answer 11

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

Question 12

What causes myotonic dystrophy?

Answer 12

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

Question 13

What do the repeat sequences in DM1 cause associated to myotonic dystrophy?

Answer 13

Cataracts, Cardiac arrythmias, Gonadal failure, Hypo IgG, Myotonia, Muscular Dystrophy, Serological changes, & Insulin resistance

Question 14

How many CTG repeats in the DM-1 gene causes phenotypic expression of the disease?

Answer 14

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

Question 15

The defect found in the DM-1 gene causing DM is a _____ type of mutation

Answer 15

gain of function; results in a toxic mRNA, however the protein is made normally (it just has overexpression/gain of function)

Question 16

What is anticipation of DM-1?

Answer 16

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

Question 17

How is DM an example of locus heterogeneity?

Answer 17

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

Question 18

Sickle cell disease can be considered to be a ______ (gain/loss) of function

Answer 18

Gain of function; hemoglobin functions normally, but in the presence of low oxygen it polymerizes (this is considered to be a gain of function)

Question 19

What is Huntington’s disease?

Answer 19

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.

Question 20

What does Huntington’s disease result in?

Answer 20

1) Progressive chorea
2) Rigidity
3) Dementia
4) Death, 10-15 after onset

Question 21

What does the age of onset of Huntington’s disease correlate with?

Answer 21

Highly variable age of onset correlates with number of tandem CAG triplet repeats in the coding region of the HD gene

Question 22

What causes Huntington’s Disease?

Answer 22

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

Question 23

Is there anticipation associated with Huntington’s disease?

Answer 23

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

Question 24

What is Kennedy disease?

Answer 24

1) Adult onset spinal bulbar muscular atrophy

2) Motor neuronopathy, but affected males can live long lives

Question 25

What causes Kennedy disease?

Answer 25

Expansion of CAG triplet in coding region f Androgen Receptor (AR) gene causes gain of function of the androgen receptor

Question 26

The Androgen receptor (AR) gene is an _____ gene that can undergo different mutations that result in ______

Answer 26

X-linked; gain or loss in function

Question 27

What is complete testicular feminization?

Answer 27

An individual undergoes a loss of function mutation in the promoter region of the androgen receptor gene, resulting in an XY female