Trinucleotide repeat diseases Flashcards
What is the distinguishing feature of a karyotype of a patient with Fragile X?
Looks like the ends of the X chromosome are broken off; in reality they have uncoiled and stain differently
What gene is affected in Fragile X?
FMR1
Describe the important structural elements of the FMR1 gene.
- 5’ CpG island
- CGG trinucleotide repeat in the first intron
How does number of repeats impact phenotype in Fragile X?
28 repeats = normal phenotype
55 - 200 = premutation but normal phenotype
> 200 = intellectual disability
How do pre-mutations expand to full mutations in fragile x?
> 55 CGG repeats are meiotically unstable in oogenesis and will expand (mitotically stable post-fertilization though)
How stable are full mutations in Fragile X?
> 200 CGG repeats are meiotically unstable in oogenesis and mitotically unstable (leading to mosaicism)
What is the penetrance of intellectual disability in affected male and female children with Fragile x?
m: 100%
f: 53%
What is the Sherman paradox?
Anomalous non-mendelian pattern of inheritance characterized by anticipation
What symptoms may Fragile X carriers express?
Male: 40% have tremor/ataxia syndrome after age 50, difficulties with movement, memory, and autonomic nervous system
Female: 20% have primary ovarian failure
Anticipation
Appearance of a genetic trait at an earlier age or with greater severity in successive generations
What trinucleotide repeat diseases have a repeat in a non-coding region?
- Fragile x (intron)
- Myotonic dystrophy (3’ UTR)
- Friedrich’s ataxia (intron)
What trinucleotide repeat diseases have a repeat in a coding region?
- SBMA (Kennedy)
- Huntington
How does increased CGG repeat length impact gene expression in Fragile x?
more CGG repeats => more methylation of upstream CpG island => transcriptional repression
What is the pattern of Fragile X inheritance?
Autosomal dominant
What is the pattern of inheritance of Friedrich’s ataxia?
Autosomal recessive
What trinucleotide repeat is associated with Friedrich’s ataxia?
Intronic GAA repeat
What are the symptoms of Friedrich’s ataxia?
- Onset < 20 yo
- Ataxia of all 4 limbs
- Cerebral dysarthia
- Absent reflexes, sensory loss, pyramidal signs
- Cardiomyopathy, skeletal deformaties
- Glucose intolerance and diabetes
How does repeat length affect Friedrich’s ataxia phenotype?
- longer length (of shorter allele) = earlier onset
What is the pattern of inheritance of myotonic dystrophy?
Autosomal dominant
What trinucleotide repeat is associated with myotonic dystrophy?
CTG in 3’ UTR
What are the symptoms of myotonic dystrophy?
- Onset 20-30 yo
- Progressive weakness and myotonia
- Cataracts
- Arrhythmia
- Hypogonadism
- Male pattern baldness
- Cognitive impairment
What mutation is associated with Complete Androgen Insensitivity Syndrome?
Loss of function mutation to the androgen receptor (x chromosome)
What is the pattern of inheritance of complete androgen insensitivity syndrome?
X-linked, sex limited
What are the symptoms of complete androgen insensitivity syndrome?
- Chromosomal males look like females
- Undescended testes, absent uterus, blind vagina
- Failure of virilization at puberty
- Aromatization of androgens to estrogens => female secondary sex characteristics
- No neurologic disease
What trinucleotide repeat is associated with SBMA/Kennedy disease?
- Expansion (11-34 => 40-62) of poly-glu tract in exon 1 of androgen receptor gene
What is the pattern of inheritance of SBMA?
X-linked recessive
What are the symptoms of SBMA?
- Onset in 3rd decade
- Progressive loss of spinal cord and bulbar motor neurons
- Muscle weakness
- Gynecomastia, reduced fertility, testicular atrophy
What trinucleotide repeat diseases are associated with loss of function mutations?
- Fragile X
- Friedrich Ataxia
What trinucleotide repeat diseases are associated with gain of function mutations?
- Myotonic dystrophy
- Fragile x associated ataxia/tremor syndrome
- huntington
- SBMA
