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1 - PBS2 > 44 - DNA Testing > Flashcards

44 - DNA Testing Flashcards

1
Q

Unstable repeat expansions

A

Characterised by an expansion of a segment of DNA within the specific gene.
Consists of repeating units of three or more nucleotides in tandem
Often trinucleotide repeats

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2
Q

Molecular basis of repeat expansion disorders

A

Gene has a normal repeat region.
When a number of repeat units increases to above the number in the normal range -> condition
Below threshold repeats are stable in germline and somatic cells
Become unstable above threshold

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3
Q

Dynamic mutations

A

Size of expansion changes

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4
Q

Anticipation

A

Expansion size of repeats increases in following generations.

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5
Q

Relationship between number of repeats and age of onset

A

Increased number of repeats lowers the age of onset

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6
Q

Mechanism of repeat expansion

A

Slipped misrepairing.
During replication, replicating strand detaches inappropriately from template.
Replicating strand slips from its proper alignment with the template strand by one repeat length.
Newly synthesised strand has one extra repeat.

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7
Q

Four examples of triplet repeat expansion disorders

A

Huntington’s
Fragile X
Dyotonic dystrophy
Friedrich ataxia

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8
Q

Class one unstable repeat expansion

A

Non-coding repeats causing a loss of protein function (EG fragile X syndrome)

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9
Q

Class two unstable repeat expansion

A

Non-coding repeats that confer novel properties on mRNA.

Leads to a toxic gain of function (EG myotonic dystrophy, fragile X syndrome associated tremor ataxia)

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10
Q

Class three unstable repeat expansion

A

Repeats in a codon that confer novel properties on the affected protein.
Leads to novel gain of function which is toxic, or overrides normal function of protein (EG Huntington’s)

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11
Q 
Characteristics of late-onset neurodegenerative disorders caused by repeat expansions 
1
2
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4
5
A

• Characterised by loss of movement control
• Variable and overlapping clinical presentation
• Late onset disorders (mostly)
• Symptoms worsen over time
• DNA testing can aid diagnosis, especially in differential
diagnosis
– Also for predictive testing (pre-symptomatic at-risk
relatives and in prenatal testing)

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12
Q

Inheritance of Huntington’s

A

Autosomal dominant

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13
Q

Prevalence of HD

A

1 in 10,000 to 20,000

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14
Q

Age of onset of HD

A

LAte onset (mean age is 40-50 years)

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15
Q

Three main classes of features of HD

A

Movement disorder
Cognitive disorder
Psychiatric/emotional disorder

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16
Q

Early features of HD

A

Clumsiness, agitation, irritability, apathy, anxiety, disinhibition, delusions/hallucinations, abnormal eye movements, depression

Very generic

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17
Q

Middle features of HD

A

Involuntary movements, chorea, trouble with balance and walking, trouble with activities that require manual dexterity, slow voluntary movements, general weakness, weight loss, speech difficulties (dysarthria), stubbornness

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18
Q

Late features of HD

A

Rigidity, bradykinesia (difficulty initiating and continuing movements), serious weight loss, inability to walk, inability to speak, danger of choking on food, inability to care for oneself

19
Q

Genetic basis of HD

A

CAG repeat in HTT gene found on chromosome 4

Repeat is in exon 1, CAG codes for glutamine

20
Q

Role of huntingtin

A

Roles in transcription (EG of brain-derived neurotrophic factor), intracellular transport of other molecules, intracellular signalling and metabolism and in reducing apoptosis

21
Q

Pathology of HD

A

Progressive degeneration and loss of medium spiny

neurons in striatum of the basal ganglia

22
Q

Molecular pathology of HD
1
2
3

A

PolyQ-huntingtin cleaved by caspases and other enzymes generating N-terminal fragments with altered conformation - these are toxic.

These form aggregates and nuclear inclusions (this might not be toxic. Might even be protective cellular response)

Loss of functional HTT and possible mRNA toxicity might also contribute to pathology

23
Q

Normal number of CAG repeats in HTT gene

A

Under 26

24
Q

Number of CAG repeats in HTT gene that has 100% penetrance for Huntington’s disease

A

Over 40 repeats

25
Q

Number of CAG repeats in HTT gene that will not affect individual, but could expand in germline cells

A

27-35 repeats

26
Q

Why is there more paternal transmission of HT than maternal?

A

Intermediate number of repeats more likely to expand in sperm than eggs.

27
Q

Something that can mitigate effect of CAG repeats

A

CCG interruptions of CAG repeats

28
Q

HD testing

A

PCR fragment analysis on capillary electrophoresis with fluorescent tag.
Look at number of repeats (on two alleles)

29
Q

Inheritance pattern of spinocerebellar ataxias

A

Autosomal dominant

30
Q

Age of onset of spinocerebellar ataxias

A

Late-onset

31
Q

Main features of spinocerebellar ataxias

A

Progressive degeneration of cerebellum, brain stem and
spinocerebellar tracts (gait, hand coordination, speech, eye
movements)

32
Q

Unusual spinocerebellar ataxia

A

SCA6.
Mutation is in a subunit of a Ca2+ channel.
No anticipation.

33
Q

Inheritance pattern of Friedrich ataxia

A

Autosomal recessive

34
Q

Prevalence of Friedrich ataxia

A

2 - 4 in 100,000

35
Q

Age of onset of Friedrich ataxia

A

Usually around puberty (mean age is 10 - 15 years, usually under 25)

36
Q

Main features of Friedrich ataxia
1
2
3

A
  • Progressive limb and gait ataxia
  • Cardiomyopathy (~65%) (often the cause of death)
  • Diabetes mellitus (~30%)
37
Q

Repeat in Friendrich ataxia

A

GAA repeat in FXN gene found on chromosome 9

38
Q

Location of GAA repeat in Friedrich ataxia

A

Located in intron 1 of FXN gene

39
Q

Effect of Friedrich ataxia GAA repeat

A

Causes abnormal DNA secondary structure or induces heterochromatin, resulting in reduced protein production

40
Q

Number of Friedrich ataxia cases attributable to repeat expansion

A

94-96%

41
Q

Effect of GAA repeat in Friendrich ataxia

A

Defect causes mitochondrial iron accumulation, leading to

oxidative damage

42
Q

Normal range of GAA repeats in Friendrich ataxia

A

5 to 33

43
Q

Affected range of repeats in Friendrich ataxia

A

66 to 1700 repeats

44
Q

Premutation range of repeats in Friendrich ataxia

A

34 to 65 repeats

1 - PBS2 (96 decks)

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