What is the role of α1-antitrypsin in normal lungs?
Acute phase reactant - levels in the lung may increase 11 fold in response to inflammation
Provides 90% of the protection against elastolytic activity of neutrophil elastase
What is the pathogenesis and presentation of lung disease in the absence of a1-antitrypsin?
Autosomal recessive disorder
Deficiency allele most common - M allele is normal
Z allele accounts for 95% of disease cases
What is the prevalence of α1-antitrypsin deficiency and its genetic basis?
70,000 affected (Mostly European decent)
Homozygote Z allele
Define the term conformational disease and explain how it applies to α1-antitrypsin deficiency
Where the allele alters confirmational stability of the protein in the absence of protease cleavage
What is the prevalence of cystic fibrosis and its genetic basis?
Most common fatal autosomal genetic disorder of whites
1000 new cases/ year
Mutations in the cystic fibrosis transmembrane conductance regulator cause CF
What is the role of CFTR in normal tissues?
ATP binding cassette (ABC) transporter of Cl- and regulator of other channels
Regulated via cAMP and ATP hydrolysis
What is the pathogenesis and presentation of disease in the absence of CFTR?
CFTR will activate epithelial Na+ channels inf pts w/ CF due to low Na+ influx
Obstructive azoospermia
Idiopathic pancreatitis
Disseminated bronchiectasis
Allergic pulmonary aspergillosis
Atypical sinopulmonary disease
Asthma
What are the goals of genetic testing?
Detect the presence of only those mutations that are known to result in compromised protein functions in the context of a given disease based on lab studies
Reserved only for individuals w/in families where the presence of disease is clear or for individuals who display several signs of a specific disease