Genetics of Triplet Repeat Disorders (Week 4--Grody) Flashcards Preview

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Flashcards in Genetics of Triplet Repeat Disorders (Week 4--Grody) Deck (16)

What does it mean that trinucleotide repeat expansions are dynamic mutations?

They can change, and are not fixed like single nucleotide mutations


Unusual aspects of inheritance of trinucleotide repeat disorders


Parent-of-origin effects

Skewed X-inactivation

Methylation effects

Incomplete penetrance

Variable expression

Premutation alleles (specific to Fragile X...)


Examples of triplet repeat disorders

Huntington disease: autosomal dominant; CAG; coding region

Fragile X syndrome: X-linked; CGG; 5' untranslated region (UTR)

Myotonic dystrophy: autosomal dominant; CTG; 3' UTR

Friedreich ataxia: autosomal recessive; GAA; intron

Spinobulbar muscular atrophy: CAG

Spinocerebellar ataxia 1: CAG


CGG repeat in Fragile X Syndrome

Normal: 6-54 repeats

Premutation: 55-200 repeats

Full mutation: 200 - >1000 repeats


Methylation in Fragile X Syndrome

Hypermethylation causes gene expression to be turned off

Alleles with >200 repeats are hypermethylated (transcriptionally repressed)

Note: patient with expanded triplet repeat but NO methylation does NOT exhibit symptoms of Fragile X Syndrome!


When using Southern blot vs. PCR to look for full mutation, what do you see?

Southern blot: see large smear because different lengths and long fragments

PCR: see no band because too long and also if CGG repeat (Fragile X) too hard to unwind because C's and G's hold on via 3 H bonds


Southern Blot for Fragile X

For females will see 2 bands (XX) and for males will see 1 band (XY)

Larger (higher up) band means premutation and even larger means full mutation


Fragile X methylation analysis

Can use BssH2 which is a methylation sensitive restriction enzyme that only cuts DNA if it is unmethylated

This is important because you could see that you have a large fragment that is unmethylated so will not cause Fragile X


Does the length of the premutation affect the incidence of full mutation in offspring?


The longer the maternal premutation, the more likely the offspring is to get the full mutation

56-59 premutation --> 13% chance of offspring with full mutation

80-89 --> 73%

100-109 --> 100%


Fragile X Syndrome

X-linked recessive/semi-dominant (some females affected)

CGG repeat in 5' UTR

Premutation expands when inherited from mother

Full mutation must be hypermethylated to cause disease

>90% have mental retardation, IQ 20-60; children are hyperactive, ADD, autistic features, hyperextensible joints, mitral prolapse; after puberty: macroorchidism, long face, large ears, prominent jaw


Fragile X premutation symptoms

Female: premature ovarian failure

Male: late-onset tremor-ataxia-dementia


Myotonic dystrophy

Autosomal dominant

Myotonia, muscular dystrophy, cataracts, hypogonadism, frontal balding

CTG repeat in 3' UTR

Mild or severe based on length of repeat

Greatest expansion when inherited from mother (this can produce severe neonatal form)


Friedreich ataxia

Autosomal recessive

GAA repeat in intron; small proportion are compound heterozygotes w/expansion on one allele and point mutation on the other

Gait disturbance in childhood, ataxia, absent reflexes, cardiomyopathy, intellectual decline


Huntington's disease

Autosomal dominant

CAG repeat in exon (>39); codes for polyglutamine tract in protein product; length of repeat inversely related to age of onset

Greatest expansions when inherited from father

Middle-age onset, choreoathetosis, dementia, psychosis


Childhood onset Huntington's disease

If repeat 100 or more

Would need expansion through father for many generations


Ethical dilemmas associated with DNA testing

Prenatal diagnosis, abortion

Risk of anxiety, depression, suicide

Testing of children for adult-onset diseases

Informed consent

Genetic privacy

Family dynamics

Risk of insurance or employment discrimination

Restrictive gene patents

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