Molecular Medicine Exam #1 - Pulmonary and Hematological Diseases

Categories of Gene Mutations

• Point mutations within coding sequences

• Mutations within noncoding sequences

• Deletions and insertions

• Structural alterations in protein-coding genes

• Trinucleotide-repeat mutations

Hereditary disorders:

Transmitted in germline; familial

Congenital

“Born with”

T/F Congenital diseases are not all genetic

True

T/F Not all genetic diseases are congential

True

Transmission patterns for single-gene disorder

• Autosomal dominant

• Autosomal recessive

• X-linked recessive

Cystic fibrosis inheritance pattern

Autosomal recessive

Cystic fibrosis

• caused by mutation in cystic fibrosis transmembrane conductance regulator (CFTR) gene, which codes for an anion channel (Cl- and bicarb)

• Results in viscous secretions in exocrine glands and in the epithelial lining of the respiratory, gastrointestinal, and reproductive tracts

Cystic Fibrosis carrier frequency

1 in 20 in people of Northern European descent

• most lethal genetic disease that affects people of this descent (1 in 2500 live births)

Chromosome that carries CFTR Gene

Chromosome 7

CFTR domains

• 2 transmembrane domains

• 2 nucleotide-binding domains (NBDs)

• regulatory R domain

CFTR function and binding process

1. Binds to epithelial cells

2. Increases levels of cAMP

3. PKA activated and phosphorylates R domain of CFTR using ATP

4. Opens Cl- ion channel

CFTR Transport throughout the cell

1. Nucleus: Chromosome 7 CFTR gene —> CFTR mRNA

2. ER: Translation and folding

3. Golgi: Processing

4. Cell surface: Function

Cystic Fibrosis pathogenesis - Lumen of sweat duct (exocrine gland)

Mutated CFTR, INCREASES NaCl concentration in sweat

Cystic Fibrosis pathogenesis - Airway (Lining of organ)

• decreased Cl- secretion

• Increased Na+ and H2O reabsorption leading to dehydrated mucus

NORMAL CFTR function in lumen of sweat duct

• CFTR opens Cl- channel, allowing for Cl- to go into the lumen from the extracellular space

• CFTR activates ENac, allowing Na+ to enter the cell (augments Na+ absorption)

NORMAL CFTR function in airway

• CFTR opens Cl- channel allowing Cl- to enter the extracellular space from the cell

• CFTR inhibits ENac, preventing Na+ entry into the cell and reduced H2O reabsorption = normal mucus

What does a mutated CFTR gene do in airways

Leads to dehydrated mucus —> defective mucociliary action (crushes cell’s cilia) and the mucus will plug the airways (leads to decreased lung function in some cases)

Describe Class I of CFTR mutation

Class:

CFTR defect:

Type of Mutation:

Describe Class II of CFTR mutation

Class:

CFTR defect:

Type of Mutation:

Describe Class III of CFTR mutation

Class:

CFTR defect:

Type of Mutation:

Describe Class IV of CFTR mutation

Class:

CFTR defect:

Type of Mutation:

Describe Class V of CFTR mutation

Class:

CFTR defect:

Type of Mutation:

Describe Class VI of CFTR mutation

Class:

CFTR defect:

Type of Mutation:

T/F the different types of CFTR mutation classes act as molecular targets dependent on genotypic variability

True

• Each CFTR mutation class affects CFTR differently and provide basis for treatment and modulatory therapy

Describe the relationship between level of CFTR function and severity of symptoms

HIGHER CFTR function = LESS Severe

• inverse relationship

<5% CFTR function symptoms

• Severe chronic sinusitis

• Severe lung disease

• High sweat chloride

• Pancreatic INsufficiency

• Meconium ileus

• Absent vas deferens

<10% - <20% CFTR function symptoms

• Moderare chronic sinusitis

• Variable lung disease

• Intermediate sweat chloride

• Pancreatic sufficiency

• Distal intestinal obstruction syndrome

• Absent vas deferens

50% CFTR function symptoms

• increased rate of chronic sinusitis

• increased rate of lung disease

• increased risk of absent vas deferens

Specific CFTR Gene mutations we have to know:

Clinical features of CF

1. Chronic sinopulmonary disease manifested by:

   1. persistent infection with CF pathogens

CF pathogens

• Staphylococcus aureus

• Haemophilus influenzae (non-treatable)