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GenGenMol > 12 Molecular Basis of Genetic Disease > Flashcards

12 Molecular Basis of Genetic Disease Flashcards

1
Q

For Novel DNA disease variants we need to do what with teh variant?

A

Confirm the pathogenesis experimentally

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2
Q

For known mutational variants we need to do what?

A

Explore the molecular basis, which is still ongoing for many diseases

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3
Q

Why are disease mechanisms important?

A

To understand disease progression.
Predict disease progression and outcomes for patients. To guide disease management for patients. To identify drug targets for therapies (primary drive).

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4
Q

What could be a drug target?

A

Literally anything. The variant is in the DNA instructions, so anything downstream of that, be it transcription, translation, protein folding, trafficking, subcellular organelles, cell signalling etc. are all potential targets.

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5
Q

There are three things we can look at to determine disease mechanisms. And they all play into each other. What are they?

A

Types of DNA variants. Mode of inheritance. Functional consequences (e.g. LOF, GOF, DomNeg).

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6
Q

What does LOF mean?

A

Loss of function is any reduced or abolish gene function

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7
Q

What are the types of Loss of Function?

A

Quantitiative loss or protein product.
Qualitative loss fo protein product.
Regulatory mutations.
Large deletions and frameshifts.

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8
Q

Name a disease caused by quantitative LOF

A

Thalassaemia

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9
Q

What globins are there?

A

embryonic, fetal and adult globins.

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10
Q

How is thalassaemia caused?

A

Mutations in HBA or HBB leading to reduced rate or no synthesis of one fo the chains making haemoglobin

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11
Q

What is a common rare disease caused by a qualitative loss of function?

A

Sickle Cell Disease

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12
Q

What’s the mode of inheritance of sickle cell anaemia?

A

AR

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13
Q

What causes sickle cell disease?

A

an SNV in HBB. GAG>GTG. Glutamic acid>Valine

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14
Q

How does an SNV in HBB lead to sickle cell disease?

A

Mutatnt beta globin makes haemoglobin tetramer stick together because of the hydrophobic properties of valine. So long chains of haemoglobin are made. This makes RBCs rigid. Microvascular thrombosis is where these rigid RBCs block blood flow.

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15
Q

Name a blood disease that is caused by a regulatory mutation

A

Haemophilia B

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16
Q

What type of inheritance of haemophilia B?

A

X-linked recessive

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17
Q

What is the genetic cause and mechanism of haemophilia B?

A

A mutation in the promoter of the F9 gene encoding factor IX. There are two binding sites around the TSS. (The first form is called Haemophilia B Leyden?)

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18
Q

Why does haemophilia B get milder at boys puberty?

A

There are two binding sites around the TSS of the F9 gene. One is ARE, which is androgen regulated, so at puberty androgen increases F9 experssion.

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19
Q

Why type of haemophilia B is lifelong?

A

Haemophilia B Brandenburg, caused by mutations in the ARE (Androgen regulated element) of F9.

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20
Q

Name a common rare disease caused by a large deletion or frameshifts

A

DMD and BMD

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21
Q

What gene has mutations in DMD and BMD?

A

Dystrophin

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22
Q

What is the inheritance of DMD and BMD?

A

X linked recessive

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23
Q

1 in how many boys are affected by DMD?

A

1 in 3000

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24
Q

What are the symptoms of DMD?

A

Muscle weakness, wheelchair use. Respiratory and cardiac involvement. Death in 20’s.

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25
Q

1 in how many boys are affected by BMD?

A

1 in 20,000

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26
Q

Clinically, what is BMD like?

A

The same as DMD but milder, can have a normal lifespan.

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27
Q

Why is DMD more severe than BMD?

A

99% of the genomic DNA of Dystrophin is intronic. Large deletions are often in the introns. But deletions that cause frameshifts are more severe and cause DMD, those that don’t just shorten the protein and lead to BMD.

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28
Q

What does dystrophin do and why does it not matter hugely if it’s shortened?

A

It’s a long chain/rod reaching from the F-actin cytoskeleton to be anchored at the cell membrane. There are many repeats in the long chain structure. Large deletions can just shorten the chain in BMD so it can still do it’s job.

29
Q

What’s a common disease that is caused by a gain in function, and increased activity of the protien?

A

Familial Hypercholesterolaemia

30
Q

What’s the inheritance pattern of FH caused by variants in PCSK9?

A

Autosomal dominant

31
Q

What does PCSK9 normally do?

A

Helps keep a homeostasis of cholesterol metabolism by surpressing LDL-R being recycled to the cell surface, so it get degraded instead.

32
Q

What are symptoms of FH?

A

High levels of LDL cholesterol, early atherosclerosis, xanthomas (cholesterol deposits on the skin).

33
Q

What normally happens to LDL in the body?

A

LDL gets degraded in the lysosome, and LDL-R that was bound to is it recycled back to the cell surface.

34
Q

Why do PCSK9 mutations lead to FH?

A

When there is too much PCSK9 activity, LDL-R is never recycled back to the surface, so LDL ends up in high amounts in the blood.

35
Q

What are some FH treatments?

A

PCSK9 inhibitors, mAbs, or siRNA.

36
Q

What is a dominant negative mechanism?

A

Where a mutant protein product disrupts the function adversely of the normal product in a heterozygote. Considered a specific type of LOF.

37
Q

How many genes for how many types of collagen in humans?

A

30 genes for 19 types…

38
Q

What motif in collagen is important to form a triple helix structure?

A

Gly-X-Y

39
Q

Where are the majority of mutations in collagen causing a dominant negative effect and why?

A

In the Gly of the Gly-X-Y motif as this dirsupts collagen processing, so the triple helix assembly is affected if there is one mutant chain and 2 normal chains in the same complex.

40
Q

Which collagens have mutations to lead to osteogenesis imperfecta type III

A

ColA1 and ColA2

41
Q

Which collagens have mutations to lead to stickler syndrome?

A

Col2A1 or Col11A1

42
Q

Which organs are affected in stickler syndrome?

A

Eye, bone, ear, face, heart

43
Q

What are the symptoms of Col4A1/A2 cerebral small vessel disease?

A

Strokes, seizures, migraines, leukoencephalopathy, vascular dementia

44
Q

The Genome is 50% repetitive seqeunces, these can be:

A

SINEs, LINEs, LTR, DNA transposons, satellites

45
Q

Satellites can be different sizes, named:

A

Micro, mini or mega satellites

46
Q

Micro satellites are how big?

A

1-4bp repeats

47
Q

What are dynamic mutations?

A

They are caused by expansion of polymorphic DNA repeats beyond a certain copy number threshold. Trinucleotide Repeat Disorders.

48
Q

Where can trinucleotide repeats occur?

A

Anywhere in a gene. the 5’UTR, intron, ORF, or 3’UTR.

49
Q

The majority of trinucleotide repeats in ORFs are what?

A

CAG glutamine repeats

50
Q

Name 9 polyglutamine diseases

A

HD, DRPLA, SBMA, and SCA1, 2, 3, 6, 7, and 17.

51
Q

Polyglutamine disorders are usually:

A

Neurodegenerative or neuromuscular. Dominant.
Caused by protein aggregation GOF.

52
Q

What are the repeat ranges for HD?

A

<26 is normal
27-35 is premutation (not stable, likely to expand)
>36 is pathogenic
>60 is juvenile HD.

53
Q

What are we not sure about in HD?

A

Whether the neuronal intranuclear inclusions caused by protein aggregates are the cause of the disease or just a consequence of the mutation

54
Q

What might be the cause of HD?

A

Maybe blocking of vesicle trafficking, or inhibition of proteasome function, or cell apoptosis, toxic titration of chaperones, affected mitochondrial function, or aggregates sequestering other important proteins

55
Q

What are some non-polyglutamine repeat disorders in non-coding regions? (These repeats can generally be longer)

A

Fragile X syndrome, FXTAS, FRAXE, FXPOI DM1, DM2, SCA8, SCA12

56
Q

What are the main symptoms of Fragile X?

A

ID and autism

57
Q

What is the expansion in fragile X?

A

CGG in the 5’UTR

58
Q

What are the expansion ranges for fragile x?

A

6-54 normal
55-200 premutation
>200 full mutation

59
Q

What gene is affected in fragile X and what protein does it encode?

A

FMR1 encoding FMRP

60
Q

What does the CGG repeat do in Fragile X syndrome?

A

Causes DNA methylation so there is a loss of FMRP leading to impaired synapse function

61
Q

What does FMRP do normally?

A

Binds to RNA, associated with the ribosome, leading to an increased expression of synaptic proteins

62
Q

Premutation FMR1 can lead to lots of RNAs that aggregate and trap lots of proteins involved in RNA binding, protein folding and nuclear integrity. What disease does this lead to?

A

Fragile X associated tremor/ataxia syndrome. Which also has memory loss and cognitive decline.

63
Q

FXTAS is what disease mechanism then?

A

an RNA gain of function

64
Q

What is anticipation?

A

Each generation repeat lengths get longer, leading to earlier symptoms and more severe disease

65
Q

How severe are haemoglobinopathies?

A

From life threatening anaemia to symptomless

66
Q

Sometimes multiple mutations lead to a disease. What is FHC caused by?

A

Two mutations in cis in MYH7. The low penetrance missense mutation makes the pathogenic variant more severe.

Similar situation in CF, two milder missense variants make a more sever phenotype.

67
Q

How can a LOF mutation in SCN5A leading to SSS be rescued?

A

By another missense mutation at R558, to enhance cell surface targeting and improve steady state activation

68
Q

Deletion of 15q11 can cause what?

A

Either Angelman’s syndrome or Prader Willi syndrome based on being inherited from the mother or father

GenGenMol (15 decks)

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