GH - Lecture 6 + GLS

This describes the level of severity for the phenotype and may be influenced bu other genes or environmental factors.

Define expression

This describes the chances that an individual will actually develop symptoms for a genetic genetic trait

Define penetrance

100% of people with the genetic mutation will develop symptoms

What is full penetrance?

Only about 60% of individuals with the genetic mutation will develop symptoms

What is mild penetrance?

The disease is 88.9% penetrant (16/18)

If the characteristic genotype for a diseases is present in 18 individuals but what only 16 develop symptoms at all, what does that say about the penetrance of the disease?

Molecular nature of the muation (missense, conservative/nonconservative, nonsense, etc.)

Function of the protein (enzyme, structural, transport, etc.)

What factors influence expression and penetrance?

loss-of-function (haplo-insufficiency, hypomorphic), gain-of-function

What are the two main categories of changes resulting from mutations?

Neomorphic (altered genetic product with new function),

Hypermorphic (increased/uncontrolled function or expression),

Antimorphic (dominant negative) (expression of antagonistic mutation which cancels out the original function of the genetic product)

What are the categories of gain-of-function mutations?

When a dominant mutation results in a genetic product which is reduced in amount or function. This is different to a heterozygote with reduced function of a genetic product, because the resulting total activity is insufficient

What is haplo-insufficieny? How is this different from heterozygosity?

FGFR3 gene

Which gene is responsible for achondroplasia and hypochondroplasia?

When activated, this tyrosine kinase receptor produces products which inhibit long-bone formation to regulate growth by inhibiting chondroblast proliferation at the epiphyseal plate.

What happens in normal FGFR3 function?

Rather than being switched on and off the FGFR is constitutively active impairing growth

What happens in achondroplasia?

80%

How many achondroplasia mutations are de novo?

g.1138G>A, g.1138G>C both result in: p.Gly380Arg

Which mutations are responsible for 99% of achondroplasia?

In the transmembrane part of the tyrosine kinase receptor

Where is the mutation located cellularly in achondroplasia?

FGFR3 is permanently active: decreased endochondral ossification, inhibited proliferation of condrocytes in growth plate, decreased cartilage matrix production

What is the cellular mechanism in achondroplasia?

in the first tyrosine kinase domain in the cell

Where is the mutation located cellularly in hypochondroplasia?

20 different mutations

How many different mutations are responsible for hypochondroplasia?

p.Asn540Lys, p.Lys650Met

Which are the 2 most common hypochondroplasia mutations?

Very similar to achondroplasia but milder phenotype

What happens in hypochondroplasia?

disproportionate limb to trunk ratio (small limbs),

trident hands,

enlarged head,

delayed motor development,

increased death during infancy

What are typical clinical features of achondroplasia?

missing growth mile stones in childhood - failure to thrive,

short stature and disproportionate limb to trunk ratio as they age

What are typical clinical features of hypochondroplasia?

This is a lethal allele

What happens in homozygous recessive individuals for achondroplasia

There is an alteration in the number of repeats of a certain 3 base pair sequence. The disease is linked to the number of repeats

What happens in dynamic muations/expansion repeat disorders?

As DNA polymerase reads the DNA strand, it may "slip" and continue to replicate the same sequence of repeats over and over resulting in an increased number of repeats in the newly formed DNA

How do repeats expand during replication?

This occurs when a number of repeats are skipped as they form a hair pin loop and polymerase skips the loop, this may be beneficial in individuals with these excessive repeat disorders

What is "forward slippage"?

CAG - glutamine

What sequence is repeated in huntingtons disease?

30-50 (earliest reported is 2 years old)

What is the typical age of onset for Huntington's?

The repeats produce "Huntington's" protein which accumulates and clumps in cells of the caudate nucleus in the brain causing atrophy and cell death - leading to chorea and other signs

What causes the pathology in Huntington's disease?

Severity increases exponentially over 10-25 years

What is the pattern of deterioration in Huntington's disease?

Cognitive decline resulting in involuntary movements and shaking

What is chorea?

Chorea, loss of memory, thinking skills, changes in personality, depression, motor impairment

What are the effects of Huntington's disease?

3-7 per 100,000

How common is Huntington's Disease?

Normal: 10-26

HD: 36-121

What is the normal vs HD number of CAG repeats?

27-41: treated with caution

27-35: intermediate alleles, they may not develop the disease but their children may

36-41: reduced penetrance - may or may not develop HD

40-55: adult onset HD individuals generally fall into this range

60+: juvenile onset, children may develop HD

What are the different levels of CAG repeats?

Something that binds to a protein to inhibit its function

What is an antisense treatment?

When each successive generation is affected earlier or more severly by a mutation

What is "anticipation"?

The father

Large expansions of CAG repeats are more likely inherited by which parent?

This is a disease that affects multiple systems and causes progressive muscular weakness and atrophy. It may have mild, intermediate or severe expression. Caused by a dynamic mutation in a CTG repeats above 37 repeats in the DMPK gene

Briefly describe Myotonic Dystrophy ( mention: general disease, severity, gene, mutation)

Walking assistance, wheelchairs, thyroxine, pain management, arrythmia, cataract removal, etc.

What is some of the management for Myotonic dystrophy?

Mild, classical, congential

What are the 3 main forms of MD?

The more repeats: the earlier the onset, the more severe the signs and symptoms, shorter the life expectancy (if severe enough)

Generally speaking, what does the number of repeats affect?

Malignant tumours arise in one or both eyes

What is retinoblastoma, broadly?

Technically, this is a autosomal recessive disorder, as 2 mutations are necessary. However, in 90% of individuals with a single mutation, the second allele with also mutate. Hence, it is classified as autosomal DOMINANT, as it shows the same inheritance patterns. (Knudson's 2 hit hypothesis)

What is special about the pattern of inheritance for retinoblastoma?

leukocoria

What is the name of the reflection in the eye seen in most photographs of individuals with retinoblastoma?

The loss of a tumour suppressor gene - retinoblastoma

What is the molecular basis of retinoblastoma?

During the replication phase it will bind to E2F, which is responsible for replication. This stops the cell cycle in the G1 phase. If the retinoblastoma gene is defective, the cell cycle continues unregulated.

How does the retinoblastoma protein work normally?

An austosomal dominant disease which produces highly pigmented patches in the skin and growth of tumours along nerves in the brain skin and other regions. May also be accompanied by learning impairment

What is neurofibromatosis 1?

1 in 3000-4000

How common is neurofibromatosis type 1?

A mutation in the NF1 gene, a tumour suppressor gene producing neurofibromin

What causes neurofibromatosis type 1?

50% de novo, 50% inherited

How is neurofibromatosis type 1 contracted?

A disease characterised by growth of non-cancerous tumours in the nervous system, which often impairs hearing, sense of balance and causes tinnitus. Most common types of tumours are vestibular schwannomas and acoustic neuromas

What is neurofibromatosis 2?

NF2

Which gene is mutated in neurofibromatosis type 2?

It produces the tumour suppressor protein Merlin. Its normal function is thought to be to stabilise membranes.

What does NF2 produce? What is its normal function?

by age 30

When does neurofibromatosis type 2 usually manifest?

1 in 33000 people

How common is neurofibromatosis type 2?

prevents cell growth by inhibiting Ras gene

What is the normal role of NF1?

loss of function. Can be missense, nonsense, insertion, deletion (less studied in type 2)

What kind of mutation occurs in both neurofibromatosis type 1 and 2? (loss of function, neomorphic, antimorphic, hypermorphic)

100% the second allele will mutate if the first is present (though many genes can play a role)

If one mutation is inherited from a parent, what is the penetrance for neurofibromatosis?

life span reduced by 8 years on average,

tumours removed surgically - may need to be repeated,

What is the prognosis for type 1 NF?

normal life span,

vestibular schwannomas removed surgically,

can cause loss of hearing,

loss of balance can cause drowning if vestibule is affected

What is the prognosis for type 2 NF?

HTT chr4

What gene is affected in Huntington's Disease and what is its location?

No, removing it is embryolethal (mouse model)

It prevents apoptosis of neuron cells,

may regulate mitochondrial function

Could Huntington's protein be removed entirely genetically to cure HD?