Autosomal Dominant Disorders

Expression

the severity or mildness of the phenotype

Things that influence expression

• environmental factors

• allelic variants in other genes

Penetrance

the chance that an individual will actually develop symptoms

Full Penetrance

fully penetrant → 100% chance of developing the disease

Partial Penetrance

partial penetrance → alleles manifest a phenotype in x % individuals

Hypomorphic AKA Loss Of Function AKA Haplo-insufficiency 

produces a protein with reduced activity

neomorphic

new activity or novel protein product

antimorphic aka dominant negative

activity or product antagonises the activity of the normal gene product

hypermorphic

produces a protein with increased activity

Features of Autosomal Dominant

• vertical degree pattern with multiple generations affected

• each affected person normally has 1 affected parent

• males and females are equally affected and likely to pass the condition on

• variable expressivity and age-related penetrance

Chances of effected child 

Sudden appearances of autosomal dominant disease? 

de novo mutations and germline mosaicism

Expansion Repeat Disorders

• dynamic mutations (increased number of repeats of a trinucleotide DNA sequence)

• can cause the resulting protein to function improperly

how does slippage and mispairing during DNA replication increase repeat number? 

1. backwards slippage

2. repeat expansion forms a hairpin

3. hairpin repeats are incorporated into DNA in the next replication

Watch video to visualise***

how are diseases inherited according to Knudson's two-hit hypothesis?

• familial = inherit 1 mutation, 2nd develops somatically

• sporadic = requires 2 somatic mutations

how is pre-symptomatic testing of family members at risk of an AD disorder done?

1. test an affected family member for the family-specific mutation

2. confirm the diagnosis of the family member at risk (acceptable if treatment is available)

3. offer pre-symptomatic testing or assess risk for recurrence

why does gene therapy work better for recessive traits?

replaces nonfunctioning genes with the correct version

How could gene therapy work in Autosomal Dominant disorders

→ Using anti-sense rna 

antisense RNA inhibits gene expression

Process of using antisense DNA

1. start with antisense siRNA complementary to an mRNA target region

2. siRNA foms a complex that recognises target region

3. target region is cleaved

4. loss of protein synthesis (loss of function)

Achronoplasia | Hypochondroplasia → Gene and Mutation

FGFR3 (fibroblast growth factor receptor 3)

Normal Function → codes for a TKR responsible for signaling growth → limits bone formation (in long bones)

Cause of Mutation → both 80% de novo

Achronoplasia | Hypochondroplasia → How does mutaton effect function

• gain-of-function (hypermorphic → receptor constitutively active)

• inhibited proliferation and hypertrophy of chondrocytes in growth plate cartilage

• increased endochondral ossification and cartilage matrix production

Achronoplasia | Hypochondroplasia → Penetrance

100% in both

Achondioplasia → Most common mutation

p.Gly380Arg

the achondroplasia mutation affects [what part] of the receptor?

transmembrane domain

Achrodoplasia → If two heterozygotes have kids 

• 2/3 affected (dwarfism)

• 1/3 normal height

why is there a higher than normal frequency of miscarriages and stillbirths in achondroplasia?

homozygosity for the mutant allele (AA) is incompatible with life

Achondroplasia | clinical features

• abnormal bone growth → short stature with disproportionately short arms and legs

• large head and prominent forehead

• trident hands

• delayed motor development

• intelligence and life span normal

with achondroplasia, why is there is an increased risk of death in infancy?

spinal cord compression/ upper airway obstruction (bone does not grow wide enough)

Hypochondroplasia | Common mutations

• p.Asn540Lys

• p.Lys650Met

the hypochondroplasia mutation affects [what part] of the receptor?

first TK domain

Hypochondroplasia | Clinical Features 

• normal birth weight and length

• disproportion in limb trunk length (mild and easily overlooked during infancy)

• typically present as toddlers or school-aged children with failure to grow

• short stature with disproportionate limbs as they age

Difference between A and Hypo chondroplasia clinical presentation. 

• no trident hands or facial features in hypochondroplasia

• motor milestones are usually normal in children with hypochondroplasia

HD | Gene and Mutation

1. HTT gene

2. glutamine (CAG) repeats in the HTT protein

HD | effect of phenotype

HTT protein aggregation in cells of the caudate nucleus→ cell atrophy and death

HD | Clinical Features

• progressive motor disability featuring chorea (jerky involuntary movement)

• cognitive decline

• mental disturbances

• changes in personality and/ or depression

• FHx consistent with AD inheritance

HD → Number of CAG Repeats | Normal

10-26

HD → Number of CAG Repeats | With HD

36-121

HD → Number of CAG Repeats | Intermediate Alleles

27-39

• the person is not at risk of developing symptoms of HD

• but may be at risk for having a child with an allele in the abnormal range

HD → Number of CAG Repeats | Alleles between 36 -39

reduced penetrance for symptomatic HD (may or may not develop symptoms)

adult onset of HD if they have 40-55 repeats

Adult on onset of HD | Number of Repeats

40-55

Juvenile onset of HD | Number of Repeats

>60

Is pentreance 100% in HD?

no

need >40 repeats for 100% penetrance

Anticipation

phenomenon in which there is increased disease severity and/ or earlier age of onset in successive generations

Anticipation in HD Transmission

• more likely in paternal transmission (with large expansions of >7 CAG repeats)

• arises from instability of the CAG repeat during spermatogenesis

HD Treatment

• no treatment or cure

• potentially gene therapy (HTT gene silencing with siRNA)

Myotonic Dystrophy | Gene and Mutation

1. DMPK gene

2. >37 CTG repeats

is penetrance 100% in Myotonic Dystrophy?

no, need >50 CTG repeats for 100% penetrance

Myotonic Dystrophy | Effected Organs

1. skeletal/ cardiac/ smooth muscle

2. eyes

3. endocrine system

4. CNS

Myotonic Dystrophy | Phenotypes

1. mild

2. classic

3. congenital

The CTG repeats increase from mild → congenital | mild has least repeats 

The age of onset decrease from mild → congenital | mild has later onset 

life expectancy decreases from mild → congenital | mild has longer life expectancy  

Management of Myotonic Dystrophy

• assistive devices (eg. ankle-foot orthoses, wheelchairs)

• symptomatic treatment

  • hypothyroidism

  • pain management

  • arrhythmia

  • cataract removal

  • hormone replacement therapy for males with hypogonadism

  • surgical excision of pilomatrixoma (benign hair follicle tumor)

Retinoblastoma | Gene and Mutation

loss of function in a tumor suppressor gene (Rb gene)

Retinoblastoma | Normal Function

Normal → Rb protein normally regulates G1 → S phase transition (cell cycle progression checkpoint)

Retinoblastoma | Mutated Function

Mutated → loss of inhibiting function → uncontrolled cell cycle progression

Tell Tale Sign of Retinoblastoma

leukocoria (white pupils, clearer in photos)

Retinoblastoma | When and How does it begin?

etal development where retinoblasts are rapidly dividing

Retinoblastoma | Inheritance Patterns 

• familial or sporadic retinoblastoma (Knudson's two-hit hypothesis)

• due to loss of function of both alleles of the RB gene

Retinoblastoma | Penetrance

90%

Why is familial form Retinoblastoma more severe?

multiple bilateral tumors vs single unilateral tumors

Familial Retinoblastoma

Sporadic Retinoblastoma 

Neurofibromatosis | Mutation

partial or complete loss of function

Neurofibromatosis | Inheritance Pattern

1. Knudson’s 2-hit hypothesis

   • 1st mutated allele is inherited

   • 2nd allele has been somatically inactivated

Neurofibromatosis | Penetrance

both 100% ( NF1 and NF2)

Lifespan for NF1 and NF2

normal for NF2 but 8 years lower for NF1

Clinical Features of NF1

• changes in pigmentation (café-au-lait)

• growth of tumors along nerves in the skin/ brain

Pleiotropy in NF1 | how does pleiotropy explain the variability of features?

Gene Locus of NF1 gene

17q12

NF1 gene | Normal Function

• tumor suppressor gene producing neurofibromin

• prevents cell growth through inhibiting the oncogene Ras

NF1 gene | Treatment

surgical removal of disfiguring or uncomfortable discrete cutaneous or subcutaneous neurofibromas

Clinical Feature of NF2

• growth of noncancerous tumours in the nervous system → hearing loss/ deafness

• vestibular schwannomas (acoustic neuromas)

gene locus of NF2

22q12.2

NF2 gene | Normal Function

• tumour suppressor gene producing merlin

• prevent cell growth through contact-mediated growth inhibition

Treatment for NF2

• surgical removal of vestibular schwannomas

• awareness of problems with balance and underwater disorientation (prevent drowning)

Germline Mutations

A mutation that occurs in gametes (eggs or sperm) and is present in each cell
of the body and can be passed onto the next generation

Lethal Allele

An allele that causes death before reproductive maturity or halts prenatal
development

Proto-oncogene

• genes that normally help cells grow and divide.

• Upon mutation it can become turned on when it is not
  supposed to be, at which point it's now called an oncogene.

• When this happens, the cell can start to grow out of control, which might lead to
  cancer

Somatic Mutation

mutation that occurs at some time during a person’s life and is present
only in certain cells and cannot be passed onto the next generation.