Monogenic diseases
Monogenic diseases (table 1) are rare diseases attributable to genetic variants with large effects on disease status. Because of the high penetrance of such variants, the disease is typically inherited in a classical Mendelian fashion (e.g. dominant or recessive). The best-known monogenic respiratory diseases are CF and α1-antitrypsin deficiency, but hundreds of rare monogenic diseases affecting the respiratory system have been described. We refer the interested reader to the Online Mendelian Inheritance in Man (OMIM) website, which is a comprehensive, authoritative and continuously updated compendium of human genes and genetic phenotypes (see Further reading).
| Gene/locus | Gene name | Chromosomal location# |
Gene product: protein function | Disease |
|---|---|---|---|---|
| CFTR | CF transmembrane conductance regulator |
7q31.2 | Ion channel: chloride transport | CF |
| SERPINEA1 | α1-antitrypsin | 14q32.13 | Serine protease inhibitor | α1-antitrypsin deficiency (COPD, emphysema, liver disease) |
| DNAI1 | Dynein, axonemal, intermediate chain 1 |
9p13.3 | Dynein arm: ciliary function | CILD1, with or without situs inversus (Kartagener syndrome) |
| CYBB | p91-phox (phagocyte oxidase): beta subunit of cytochrome b, component of the phagocyte NADPH oxidase complex |
Xp11.4 | Killing of microbes in phagocytes by generation of reactive oxygen species |
CGD, X-linked |
| CYBA | p22-phox (phagocyte oxidase): alpha subunit of cytochrome b, component of the phagocyte NADPH oxidase complex |
16q24.3 | Killing of microbes in phagocytes by generation of reactive oxygen species |
CGD, autosomal recessive |
| SFTPC | Surfactant, pulmonary-associated protein C |
8p21.3 | Surfactant proteins are essential for lung function, preventing lung collapse by lowering surface tension |
Respiratory distress syndrome of prematurity |
| SFTPB | Surfactant, pulmonary-associated protein B |
2p11.2 | Surfactant proteins are essential for lung function, preventing lung collapse by lowering surface tension |
Respiratory distress syndrome of prematurity |
Table 1 – Monogenic respiratory diseases (inherited in a Mendelian fashion). Only seven out of more than 100 known monogenic respiratory diseases are presented as illustration. #: p refers to the short arm of the chromosome. q refers to the long arm of the chromosome. The location numbers after p and q reflect the relative distance to the centromeres of the chromosomes (numbering by convention). CF: cystic fibrosis; COPD: chronic obstructive pulmonary disease; CILD1: ciliary dyskinesia, primary 1; NADPH: nicotinamide adenine dinucleotide phosphate; CGD: chronic granulomatous disease.
Cystic fibrosis
CF is an autosomal recessive genetic disorder (i.e. both inherited copies of the gene need to be mutated in order for disease to result; or to put it another way, one healthy copy of the gene is enough to prevent CF), caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR ) gene on chromosome 7. The CFTR protein is an ion channel that regulates transport of chloride ions (Cl-) in epithelial cells in the airways, as well as in the pancreas, liver, intestine and skin. More than 1000 mutations of the CFTR gene have been described. In Europe, the most common is the ΔF508 mutation (a deletion of three DNA bases). The resulting CFTR protein has a missing amino acid (phenylalanine) in position 508. One in 25 people of European descent carries one mutant allele of CFTR, and one person in 2000–3000 is affected by CF. The various CFTR mutations cause different CFTR protein defects, which impair transport of chloride and sodium across epithelial surfaces, leading to thick viscous secretions (e.g. mucus or phlegm).
CFTR modulators and potentiators are drugs that aim to correct the underlying defect that leads to CF by modifying the function of the CFTR protein. Since the therapeutic effects of CFTR modulators are based on individual protein defects, knowledge of the genotype of both alleles of the CFTR gene is necessary for appropriate patient selection. As an example, ivacaftor, which was approved for use by the US Food and Drug Administration in January 2012, targets the specific CFTR mutation G551D (in which glycine in position 551 is substituted with aspartic acid), improves lung function and reduces respiratory symptoms and pulmonary exacerbations in patients with CF who have at least one G551D CFTR mutation.
α1-antitrypsin deficiency
α1-antitrypsin is a protease inhibitor, produced mainly in the liver, which protects the lungs against proteolytic damage by the enzyme neutrophil elastase. α1-antitrypsin is encoded by the SERPINA1 gene (also known as PI). Like CF, α1-antitrypsin deficiency is an autosomal recessive inherited disorder affecting 1 in 2000–5000 persons in Europe. It increases the risk of liver disease, COPD and emphysema. Those with two copies of the most severe “Z” mutation (PI ZZ genotype) have very low serum protein levels of α1-antitrypsin. Cigarette smoking greatly increases the risk of COPD in α1-antitrypsin-deficient patients, leading to severe, early-onset emphysema due to destruction of alveolar septa in the lung as a consequence of the protease–antiprotease imbalance.
Primary ciliary dyskinesia
Primary ciliary dyskinesia (PCD), or immotile cilia syndrome, is a genetically heterogeneous autosomal recessive disorder, caused by loss of function of different parts of the cilia, which line the epithelial cells of the airway mucosa and are responsible for clearing secretions and foreign material. Patients with PCD suffer from recurrent upper and lower respiratory tract infections, often leading to bronchiectasis, an abnormal widening of the airways. About half of people with PCD have Kartagener syndrome, in which PCD is combined with situs inversus (a condition in which the position of the major organs is a mirror image of the normal arrangement).
Other monogenic diseases encompass diseases caused by mutations in surfactant proteins, which are crucial in decreasing tension forces during breathing. Dysfunction of surfactant caused by mutations in surfactant protein genes leads to respiratory distress syndrome of prematurity. Mutations in cytochrome b, an enzyme involved in killing microbes in phagocytic cells, predispose individuals to recurrent respiratory infections (see the section on chronic granulomatous diseases later in this chapter).
