Molecular pathology: consequences of gene mutations at gene regulation level Flashcards

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1
Q

When is a DNA sequence change pathogenic?

A

Deletions, nonsense, and frameshift mutations are pathogenic mutations.

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2
Q

What is a polymorphism?

A

Sequence variation

Not all are pathogenic

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3
Q

When is a missense mutation more likely to be pathogenic?

A

When it affects a functionally important part of the protein.

If the amino acid is a conserved over evolution it is more likely to be important

If amino acid substitutions are non-conservative (polar for non polar, acidic for basic) they are more likely to be pathogenic.

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4
Q

What is an important part of a missense mutation that must be identified?

A

How severe the effects of the missense mutation are.

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5
Q

What is a loss of function mutation?

A

When there is a total loss of function resulting from total absence of the protein

Caused by any mutation which results in inactivation of the protein giving the same clinical result.

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6
Q

What type of activity does the ATM gene have?

A

Has a PI-3 kinase like domain

Therefore acts as a kinase phosphorylating other protiens (signalling protein)

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7
Q

How does the ATM kinase activity come about?

A

Has to be induced by DNA damage

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8
Q

How can ATM kinase activity be measured?

A

Immunoprecipitate the ATM protein using an ATM Ab and use it to phosphorylate a protein target (P53) in vitro.

Use a phosphospecific antibody

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9
Q

What do phosphospecific antibodies do?

A

Recognise the phosphorylated proteins but not the unphosphorylated formats.

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10
Q

What occurs to activity if proteins over time?

A

The activity changes over time
eg. ATM activity of phosphorylation increases over time
Other kinases can also phosphorylate ATM targets

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11
Q

What causes band shifts in data?

A

When a phosphorylated protein has a new molecular weight due to its phosphorylation.

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12
Q

What are some possible consequences of mutant ATM protein?

A

May have some retained function:
Allowing some degree of normal response to radiation
Could affect level of radiosensitivity -measurable
Gain of function
Altered interactions with other proteins

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13
Q

Give a consequence of having residual activity of ATM protein?

A

Increasing level of chromosome damage with decreasing ATM kinase activity.

ATM mutation causing cancer

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14
Q

What is Haploinsufficiency?

A

For most gene products, half the amount of protein is sufficient for normal function.

For other gene products, 50% of the normal level is not enough for normal function and haploinsufficiency produces an abnormal phenotype

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15
Q

What are dominant negative effects on alleles?

A

A non-functional mutant polypeptide can interfere with a normal protein from the normal allele gibing a dominant negative effect.

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16
Q

What conclusions can be drawn when there is no protein expression at all of prognosis?

A

Associated with classical disease

Leads to classical deteriation

17
Q

What conclusions can be drawn when there is some protein expression for prognosis?

A

May be associated with a less severe form of the disease.
Difficult to suggest to a patient this will mean a better prognosis.
Need a lot of data

18
Q

Why is cystic fibrosis a very variable disease?

A

Due to the influence of modifying genes and how other proteins are interacting within the mechanisms.

19
Q

What evidence is there for possible modifying genes in ataxia telangiectasia?

A

No neurodegeneration when there is no ATM protein present.

20
Q

What is locus heterogeneity?

A

Where the same disease can be caused by a mutation in a different gene.

21
Q

What is hMRE11?

A

An essential gene which is required for life

22
Q

What is the best candidate approach?

A

Where you test for other possible candidates leading to the dysfunction of a gene when the original idea mutation is not the cause