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Flashcards in Pathogenic DNA Variants Deck (37):

What sort of mutation is a frequent contributor to genetic disease? What mutations are not usually contributors?

Point mutations are by far the biggest one
Satellite and minisatellite changes are not generally associated with disease

Also, de novo genetic changes that cause single-gene disorders are very rare


Most individuals have very different/ large numbers of changes as compared with the reference genome. How many variants are predicted to cause loss of function of a gene?

Around 100- these would be caused by nonsense mutations, splice site variants, small indels causing framshifts, large deletions


Who's Craig Venter?

One of the original people to have their genome sequenced- found many differences to reference genome including 317 genes in which some variants have been identified as pathogenic


Most of the variation in our DNA is without consequence. Give two explanations/reasons why this is the case.

Only a small % of our genome is functionally important
Some genes are present in multiple copies


Most pathogenic mutations are single nucleotide substitutions which can lead to what?

Change in the sequence of the gene product (loss-of-function or gain-of-function)
or change in the amount of gene product


What is a classic example of a genetic disease caused by a single point mutation in the protein coding region? Where is the mutation and how does it affect this molecule?

Sickle cell anaemia- alteration in the charge of the surface beta-globin subunit within the haemoglobin tetramer- an acidic glutamic acid residue is replaced by a valine. This hydrophobic valine residue interacts with the hudrophobic patch on another beta-globin chain leading to the formation of fibrils that precipitate in the red blood cell, leading to sickling and inability to carry oxygen


Point mutations that affect RNA splicing are more tricky to analyse. Mutations of splice-site consensus (donor or acceptor) can lead to the splicing machinery doing what?

Skipping a whole exon or retaining a whole intron. The resulting mRNA encodes a different amino acid sequence and frequently there is a translational frameshift


Name a genetic disease related to blood that occurs because of a mutation outside the reading frame

Thalassemias- defects in synthesis of alpha or beta-globin due to splicing errors


What is a latent or cryptic splice site? When is it used?

Sequences that nearly match the optimal splice site consensus- these can be used if the real splice sites are mutated. These can also become activated by mutations


How can missense mutations or silent mutations have a pathogenic effect when they do not affect the translated product? Give an example of when this has occured.

Even if cryptic sites are in exons, these mutations may activate these sites and therefore alter RNA splicing

E.g Limb girdle muscular dystrophy creates splice site in exon 16 and thus a premature stop codon


How is cystic fibrosis caused by a mutation affecting RNA splicing?

Mutation in the CFTR gene causes activation of a cryptic splice site


Most diseases are due to SNPs however can also be triggered by repetitive DNA (microsatellites). How do tandem repeats WITHIN coding regions cause disease?

Note, there are many tandem repeats in the whole genome just not within the coding region due to selective pressure (germline mutations in coding sequences do not survive)

They are liable to pathogenic mutations due to susceptibility to slippage. Small insertions and deletions often lead to frameshifts

Recombination at these repeats can lead to large scale deletions and insertions

Spontaneous retrotransposons can insert into cDNA


Mutations in tandem repeats within the coding region are not classic polymorphisms within populations. Can they be inherited in families?

Mutant alleles are inherited stably within families


Give an example of a genetic disease caused by a frame shift caused by replication slippage in the GJB2 gene.

Autosomal Recessive Congenital Hearing Loss


What can recombination within introns of the dystrophin gene lead to?

Duchenne muscular dystrophy (caused by a deletion that caused a frameshift)- a severe and progressive X-linked recessive muscular dystrophy that results from deficiency of the dystrophin protein- people only live until 30 with this condition

Becker muscular dystrophy is a milder version (not caused by deletion that did not cause a frameshift)


Many genes contain an array of tandem trinucleotide repeats in coding regions. What may this indicate?

A functional domain within a protein e.g transcriptional activation domain


What may a change in the number of these trinucleotide repeats cause?

No frameshift but may change the function of the resulting protein


What two changes to trinucleotides are known to change the function of the resulting protein?

Polyalanine expansions which are small and cause loss of function
Polyglutamine expansions which are big and dynamic (gets bigger every generation) cause gain of function


What are dynamic mutations?

Repeat expansions which frequently expand further in subsequent generations so the age of onset and severity of symptoms become worse with each generation


Are dynamic mutations stable?

Highly unstable and the diseases caused are very heterogeneous- different sizes, locations etc.


Fragile sites on chromosomes are liable to chromatid breaks. In what conditions are common ones seen under? Where are rare ones seen (less than 5% of pop have these)?

Common fragile sites are found in all individuals when cells are cultures under conditions of replication stress and involve both homologues and instrinsic parts of the chromosome structure

Rare ones are found just one of the chromosome homologues


Are rare fragile sites associated with disease?

Most are not with exceptions being:

FRAXA FMR1 gene-classic fragile X syndrome
FRAXE FMR2 gene- fragile X E syndrome- mild retardation
FRA11B- Jacobsen chromosome deletion syndrome

These are caused by tracts of trinucleotide repeats being amplified beyond a critical point


Expansions of CAG repeats can cause neurodegenerative disorders. What are these groups of disorders collectively called? (many possible answers)

Polyglutamine disorders, PolynGln disorders, PolyQ disorders and CAG disorders


Are PolyGln disorders polymorphic in the population? Do they show dynamic expansion and anticipation? Is there a correlation between the number of repeats and age onset?

Yes they are polymorphic (unlike PolyAlanine repeats)
They do show dynamic expansion and anticipation and there is a loose correlation


What is Huntington disease? What are the symptoms associated with it?

Autosomal dominant ingerited disease caused by unstable length mutation in huntingtin gene on chromosome 4

Progressive chorea, dementia and psychiatric symptoms

The abnormal protein product is toxic to neurons


Fragile X Syndrome results from an expansion of a CGG sequence in the 5' UTR of the FMR1 gene. What does this gene regulate?

Synapse development- does this by binding to appropriate mRNAs to inhibit translation


Fragile X syndrome:

Normal- 5-54 tandem copies of CGG repeat units
Abnormal- 200-1000

What is the risk to those who have 55-200 repeats?

They themselves may not suffer but due to its instability, their children may


What are the symptoms of Fragile X Syndrome?

What causes it?

Intellectual disability (especially in males) and behavioural abnormalities

Expanded CGG can become targets for cytosine methylation leading to epigenetic silencing of the gene
Point mutations occasionally cause loss of function too


Mytotonic dystrophy results from a CTG expansion in the DMPK gene. What does this gene encode? Is this affected in the mutated form? What is affected?

A protein kinase which is not affected at all. This disease is a gain-of-function disease in which the expanded repeat interacts with the RNA-binding splicing regulators that are normally involved with splicing of the mRNAs that encode key muscle proteins. These splicing regulators are thus sequestered away from their normal target mRNAs, resulting in important loss of muscle proteins and consequent muscular dystrophy

Similar effect can be caused by expansion in ZNF9 gene


Are the following modest expansions or large expansions?

Huntington disease, Kennedy disease, Spinocerebellar ataxia diseases

Fragile X Syndromes and Myotonic dystrophy

First group are modest

Second are large scale


Loss-of-function mutations:

How are the effects of these seen?
What is their pattern of inheritance?
What are the mechanisms or is it mutational heterogeneity?

By inactivating the normal function
Usually recessively inherited but some can show dominant inheritance due to haploinsufficiency or dominant-negative effects
Mutational heterogeneity- many different ways to inactivate a gene/its products


When is dominant inheritance seen in loss-of-function mutations?

When 50% of the output of a single allele is not sufficient for normal cellular function (aka haploinsufficiency; often seen when mutation affects a gene whose protein product us dosage-sensitive)

E.g PAX3 gene mutations


When are dominant-negative effects seen?

When the protein product of a mutant allele interferes with the protein product of the wild type allele- proteins that function as oligomeric structures often show dominant-negative effects


In dominant-negative effects, are null alleles or missense mutations more severe in their effect?


E.g Procollagen production defective more when there is a missense mutation than null/deletion


Why are gain-of-function mutations less common than loss-of-function?

They are usually lethal in early development- many are seen as cancers (somatic mutations)


Do gain-of-function mutations show mutational homogeneity?

Yes, only appear in same places


What does the alpha1-antitrypsin gene encode?

What does the mutated version do?

A protein which interacts with elastase and inactivates it thus protecting tissues from high levels of it

The mutant has a specificity for thrombin instead of elastase. It inactivates it causing lethal bleeding disorders as clotting cannot occur