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Human Molecular Genetics 2004 13(Review Issue 2):R207-R215; doi:10.1093/hmg/ddh252
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Human Molecular Genetics, Vol. 13, Review Issue 2 © Oxford University Press 2004; all rights reserved

Genetic disorders influencing lung formation and function at birth

Jeffrey A. Whitsett*, Susan E. Wert and Bruce C. Trapnell

Department of Pediatrics, Division of Pulmonary Biology, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, OH 45229-3039, USA

Received July 2, 2004; Accepted July 23, 2004


   ABSTRACT
TOP
 ABSTRACT
STAGES OF LUNG MORPHOGENESIS
 PULMONARY SURFACTANT IS REQUIRED...
 DISORDERS OF SP-B GENE...
 DISORDERS OF THE SP-C...
 DISORDERS OF THE ABCA3...
 SUMMARY
 REFERENCES
 
Adaptation to air breathing at birth is dependent on formation and function of the lung. Lung morphogenesis is a complex process dependent on precise temporal–spatial control of cell proliferation, differentiation and behavior mediated by autocrine–paracrine signaling that instructs transcriptional processes during organogenesis. Mutations in genes causing severe, and often lethal, lung malformations include those in the sonic hedgehog, fibroblast growth factor and thyroid transcription factor-1 pathways. Mutations in genes regulating surfactant homeostasis, necessary for reduction of surface tension in the alveoli, cause lethal respiratory distress at birth or interstitial lung disease in childhood. Inherited disorders of the surfactant system that affect neonatal respiratory adaptation at birth include hereditary surfactant protein B deficiency, mutations in surfactant protein C and the ABCA3 transporter.

Formation of the vertebrate lung represents a remarkable evolutionary step enabling adaptation of vertebrates to air breathing. Morphogenesis of the lung begins with the evagination of cells from the foregut endoderm into the splanchnic mesenchyme. The lung buds elongate and branch to form trachea and mainstem bronchi. Continued stereotypic branching and budding produce the conducting airways that lead to subdivided saccules which form the alveolar region of the peripheral lung. Although fluid-filled in utero, immediately after birth, the lung is filled with inhaled gases. Thereafter, the organism is entirely dependent on gas exchange provided by the lung. Perinatal adaptation to air breathing is dependent on the generation of normal lung structure, the precise regulation of ventilation and perfusion and the production of pulmonary surfactant required for reduction of surface forces generated at the gas–liquid interface in the alveoli. Failure of lung formation and surfactant function results in respiratory failure at birth. This review will consider genetic causes underlying abnormalities in lung formation and function that lead to respiratory failure in the perinatal period.


   STAGES OF LUNG MORPHOGENESIS
TOP
 ABSTRACT
 STAGES OF LUNG MORPHOGENESIS
PULMONARY SURFACTANT IS REQUIRED...
 DISORDERS OF SP-B GENE...
 DISORDERS OF THE SP-C...
 DISORDERS OF THE ABCA3...
 SUMMARY
 REFERENCES
 
Formation of the vertebrate lung has been subdivided into five distinct periods on the basis of the anatomic changes that occur in lung architecture (Fig. 1) (1). The nature of abnormalities in lung formation associated with pulmonary malformations is influenced by the timing and extent of disruption of gene function during morphogenesis (Table 1).



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  		Figure 1. Anatomic classification of periods of lung morphogenesis.

 

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  		Table 1. Stages of human lung morphogenesis and associated disorders
 
Embryonic period (3–7 weeks)
During the embryonic period, tracheal–bronchial tubules are formed from the pulmonary diverticulum that forms at the medial tracheal–laryngeal sulcus in the ventral wall of the foregut. Branching of the trachea produces two lobar bronchi on the left and three on the right side, defining the lobar anatomy of the human lung. The esophagus and trachea separate, bronchial tubules subdivide to form the bronchopulmonary segments, and the splanchnic mesenchyme undergoes differentiation and organization to form blood vessels, lymphatics and other supporting structures, including tracheal–bronchial cartilage and smooth muscle. Vascular anastamoses link vessels formed by angiogenesis and vasculogenesis with the larger pulmonary vessels that flow to and from the atria. Defects in embryonic lung formation include tracheal–esophageal atresia/fistula and pulmonary agenesis.

Pseudoglandular period (7–17 weeks)
During this period of development there is rapid expansion of the conducting airways and peripheral lung tubules which continue to branch and bud to form the acinar tubules. The expansion of these small tubules in the periphery of the lung produces a glandular appearance. The peripheral lung mesenchyme thins and becomes increasingly vascularized. Neuroendocrine bodies, nerves, and organized smooth muscles are observed in the developing airways. Cartilage rings continue to form around the segmental bronchi. The pleura–peritoneal cavity closes, the diaphragm thickens and becomes increasingly muscularized. Defects in closure of the diaphragm cause diaphragmatic hernia with ipsilateral pulmonary hypoplasia.

Canalicular period (16–26 weeks)
The fluid-filled tubules expand to form saccules and the capillary/vascular channels and presumptive airspaces come into increasingly close apposition to form the primordial gas exchange region of the peripheral lung. The pulmonary mesenchyme thins as more peripheral lung tubules are formed. Differentiation of the respiratory epithelium begins. At this time, components of the surfactant system are first observed, including the production of lipids and proteins that will be necessary for surfactant function at birth. In the peripheral lung saccules, cuboidal type II cells express surfactant proteins and lipids. Squamous type I cells differentiate and are closely associated with pulmonary capillaries in the peripheral gas exchange region of the acini. Preterm babies born after 23–24 weeks gestation suffer the implications of pulmonary immaturity and respiratory distress syndrome (RDS), but may survive when provided intensive care. Oligohydraminos, whether related to renal anomalies or loss of amniotic fluid, is often associated with lung hypoplasia during this period.

Saccular period (22–36 weeks)
Continued proliferation and expansion of the acinar tubules occur during the saccular period. The distal saccules thin as pulmonary capillaries and squamous cells of the epithelium form the gas exchange region. Epithelial cells of conducting airways are increasingly differentiated. Ciliated cells and subsets of distinct, non-ciliated columnar epithelial cells are distinguished. Lamellar bodies, containing surfactant lipids and proteins, are prominent in type II epithelial cells that line peripheral saccules. The surface area of the gas exchange region increases dramatically in preparation for birth. During this stage, peripheral saccules are often able to support respiration after preterm birth. Additional alveoli septae form, which further subdivide into peripheral saccules later in this period. Submucosal glands become prominent in the conducting airways. As in the canalicular period, lack of amniotic fluid, whether related to renal anomalies (Potter's syndrome) or rupture of amniotic membranes, may cause lung hypoplasia during this period. RDS, caused by surfactant deficiency, is a frequent complication of preterm birth during this period.

Alveolar period (36 weeks to maturity)
This period begins near the time of birth and continues to maturity, at which time alveolar septation is completed. The adult lung is comprised of approximately 300 million alveoli that create a gas exchange surface area of ~10 m2. During the alveolar period, increasing septation and continued thinning of stromal vascular elements create the alveolar–capillary structures characteristic of the mature lung. Abnormalities of alveolarization cause alveolar simplification with enlarged alveoli in the postnatal period.

Autocrine–paracrine and transcriptional signaling during formation of the lung
As in morphogenesis of other organs, cell proliferation, commitment, differentiation and interactions are influenced by complex autocrine–paracrine signaling that regulates gene transcription and cellular behavior (reviewed in 2–4). An increasing array of signaling molecules, receptors and transcriptional modulators that play critical roles in lung morphogenesis are being identified in the mouse. Mutations in genes encoding some of these molecules have been linked to the pathogenesis of severe lung disease at the time of birth. In general, the timing and function of these signaling networks influence the extent and characteristics of the malformations caused by perturbation of each pathway. Table 2 lists a number of genes now known to be associated with severe lung malformations. As in other tissues, genes function in complex networks that regulate cell fate and functions. Branching morphogenesis and proximal–distal patterning of the lung are dependent on signals modulated through fibroblast growth factor (FGF) (5), ß-catenin (6), BMP-4 (7) and sonic hedgehog (SHH) (8) pathways. Transcriptional factors playing important roles in lung morphogenesis include thyroid transcription factor-1 (TTF-1) (Nkx2.1) (9), GATA-6 (10), Foxa2 (11), Foxj1 (12), Foxf1 (13), RAR{alpha}/ß (14), Hox-b5 (15,16) and Gli family members (17) (reviewed in 18). During alveolar development, FGF signaling via FGF-R3/4 (19), PDGF{alpha} (20), Foxa2 (11) and GATA-6 (10) play important roles. Likewise, mutations in the elastin gene and defective biosynthesis of heparin-sulfated proteoglycans perturb alveolarization (21,22). Lung lobulation is influenced by genes that influence left–right symmetry, including LFTY-1, NODAL and GDF-1 (23).


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  		Table 2. Genes and pulmonary malformation and dysfunction
 
Role of the SHH pathway in lung morphogenesis
Mutations in the SHH pathway have been implicated in syndromic congenital malformations affecting many organs in humans including the lung (24,25). SHH is produced and secreted by epithelial cells in the embryonic lung buds. During early embryonic periods, SHH is produced in the ventral side (tracheal) of the dorsal–ventral boundary between the trachea and esophagus, and is critical for separation of the trachea and esophagus. SHH is proteolytically cleaved and interacts with hedgehog interacting protein (HIP) and receptors (patched and smoothened) that activate Gli transcription factors including Gli1, Gli2 and Gli3 in target cells (26). Disruption of SHH/Gli2/3 and HIP in the mouse caused severe lung malformations (17,24–26). Deletion of SHH caused TE fistula, inhibited branching morphogenesis and disrupted pulmonary vascular development (24–27). Local deletion of SHH before E12.5 in respiratory epithelial cells of the developing mouse lung caused abnormalities in tracheal–bronchial cartilage formation, inhibited smooth muscle differentiation and perturbed branching morphogenesis (27).

Clinical syndromes with pulmonary malformations have been linked to SHH signaling pathways, including Pallister–Hall (MIM 14650), VACTERL (MIM 276950) (vertebral, anal, cardiac, tracheal–esophageal, renal, limb) and Smith–Lemli Opitz (SLO) (MIM 270400) (28–30). Pallister–Hall syndrome is inherited as an autosomal-dominant disorder and is associated with mutations in the GLI3 gene on chromosome 7p13 (31). SLO syndrome, MIM 270400, is caused by mutations in {Delta}-7-dehydrocholesterol reductase (DHCR7), an enzyme required for cholesterol synthesis (32). Disruption of DHCR7 causes lung hypoplasia and respiratory failure in mice (33), perhaps mediated by changes in SHH activity. Cholesterol esterification influences SHH processing and range of activity (34).

FGF signaling and lung malformations
FGF signaling plays a critical role in lung morphogenesis. In the mouse, targeted deletion of FGF-10 causes lung agenesis with formation of a rudimentary tracheal–bronchial pouch (35). FGF-10 is produced by the mesenchymal cells at the edges of the lung bud and signals via FGF-R2IIIb receptors on the endodermally derived cells of the lung buds (36). Deletion of FGF-R2IIIb or inhibition of FGF signaling via expression of Sprouty, an intracellular FGF-signaling inhibitor (35) or FGF mutant receptors that inhibit receptor signaling, blocks branching morphogenesis of the lung (5,37–39). FGF-signaling is required at precise times during lung morphogenesis for formation of the peripheral lung (38,39). Other FGF family members, including FGF-1, FGF-7, FGF-9 and FGF-18, are expressed during lung morphogenesis. Targeted deletion of FGF-9 causes lung hypoplasia in the mouse (40). Increased expression of FGF-18 in respiratory epithelial cells of the lung perturbed branching morphogenesis and caused tracheal–bronchial cartilage malformations (41). Similar malformations of tracheal–bronchial cartilage have been associated with tracheal–cartilaginous sleeve syndrome (42). Abnormal tracheal–bronchial cartilage rings are associated with Crouzon (MIM 123500), Apert (MIM 101200), Pfeiffer (MIM 101600) and Carpenter syndrome (MIM 101600).

Thyroid transcription factor-1
TTF-1 is an Nkx2.1 member of a family of homeodomain-containing transcription factors that were initially recognized for its role in thyroid and lung epithelial-specific gene expression (43,44). Deletion of TTF-1 in the mouse caused thyroid and lung abnormalities with associated tracheal–esophageal fistula and dysgenesis of the peripheral lung resulting in respiratory failure at birth (9,45). Heterozygous deletions of 14q, a region that includes the TTF-1 gene (TITF1), have been associated with thyroid dysfunction, lung disease, CNS defects and movement disorders (46). Mutations in TTF-1 were associated with benign hereditary chorea (MIM 118700) and caused hypothyroid and respiratory failure in newborn infants (47,48).

Other clinical conditions affecting respiration at birth
The analysis of genes and pathways that are critically involved in lung morphogenesis is subject to active study. Knowledge of the roles of specific genes and pathways in the pathogenesis of lung diseases that affect perinatal lung adaptation is likely to expand rapidly in the future. Genes and pathways involving organogenesis of many organs will also affect lung structure. However, perturbation of pathways that contribute to the unique structures and functions in the lung may influence perinatal survival. Table 1 lists a number of relatively common clinical conditions that affect perinatal pulmonary adaptation whose molecular pathogenesis remains to be discerned.


   PULMONARY SURFACTANT IS REQUIRED FOR POSTNATAL ADAPTATION
TOP
 ABSTRACT
 STAGES OF LUNG MORPHOGENESIS
 PULMONARY SURFACTANT IS REQUIRED...
DISORDERS OF SP-B GENE...
 DISORDERS OF THE SP-C...
 DISORDERS OF THE ABCA3...
 SUMMARY
 REFERENCES
 
Pulmonary surfactant is required for adaptation to air breathing after birth, reducing surface tension at the air–liquid interface in the alveolus to maintain lung volumes during the respiratory cycle (49). Deficiency of pulmonary surfactant is associated with RDS in preterm infants, a common cause of infant morbidity and mortality. Pulmonary surfactant is a lipid/protein complex that is synthesized by type II epithelial cells lining the alveoli of the lungs (Fig. 2). Surfactant lipids, predominantly phosphatidylcholine, and the surfactant proteins B (SP-B) and C (SP-C) are co-transported to lamellar bodies, the major intracellular storage organelle of pulmonary surfactant (49,50). Lamellar bodies are secreted into the airspace in response to stretch, ß-adrenergic and purinergic agonists. After exocytosis, lamellar bodies unravel and undergo a dramatic change in ultrastructural morphology, producing tubular myelin that represents the major extracellular pool of surfactant lipids from which mono- and multi-layered films are formed. The lipid-rich films spread at the air–liquid interface in the alveoli and reduce surface tension, preventing alveolar collapse. Intracellular and extracellular surfactant pool sizes are precisely maintained by the regulation of synthesis, secretion, reuptake, reutilization and catabolism (49–51).



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  		Figure 2. Pulmonary surfactant metabolism and homeostasis. The genes encoding SP-A, Pro-SP-B and Pro-SP-C are transcribed in the nucleus (N) of alveolar type II epithelial cells, translated into nascent polypeptides in the endoplasmic reticulum (ER) and processed in the Golgi (G) network (Processing). SP-B and SP-C are assembled into lamellar bodies along with surfactant phospholipids, the transport of which may be regulated by the ABCA3 transporter molecule, which is found in the limiting membrane of these organelles. SP-A is secreted via non-lamellar body secretory vesicles. Following exocytosis of lamellar bodies and secretory vesicles into the alveolar surface liquid (Secretion), lamellar bodies assemble into structures known as tubular myelin. Large and small aggregate particles are formed. Phospholipids from these extracellular structures move to form a continuous surfactant film that lines the alveolar spaces and airways with polar heads oriented toward the liquid and acyl chains toward the air. Surfactant large aggregate forms extracellular lamellar bodies and tubular myelin, all have surface-active properties. Surfactant is inactivated by mechanical and biological processes and converted into the surface-inactive, small aggregate which is taken up by alveolar type II cells, and reutilized (Recycling) or catabolized (not indicated). Alveolar macrophages internalize (uptake) and degrade (catabolism) small surfactant aggregate remnants.

 

   DISORDERS OF SP-B GENE (SFTPB)
TOP
 ABSTRACT
 STAGES OF LUNG MORPHOGENESIS
 PULMONARY SURFACTANT IS REQUIRED...
 DISORDERS OF SP-B GENE...
DISORDERS OF THE SP-C...
 DISORDERS OF THE ABCA3...
 SUMMARY
 REFERENCES
 
Mutations in the human SP-B gene (SFTPB) cause surfactant dysfunction and lethal respiratory distress in full-term infants. Surfactant protein B is a 79 amino acid, cationic polypeptide that is produced by proteolytic processing of a 381 amino acid precursor as it is trafficked through the endoplasmic reticulum, Golgi apparatus, multivesicular bodies to the lamellar bodies where the active peptide is stored (49,50). SP-B and SP-C are packaged together with surfactant lipids in the lamellar bodies and are secreted into the alveolus. The active 79 amino acid peptide is amphipathic and interacts strongly with surfactant phospholipids. SP-B is fusogenic, creating extended lipid layers (monolayers and multilayers) that form highly stable films in the alveoli. SP-B enhances the spreading and stability of surfactant lipids and is critical for surfactant tension reduction during respiration. The importance of SP-B in pulmonary homeostasis was shown in SP-B gene knockout mice (Sftpb–/–) and in infants bearing mutations in the SFTPB gene (52,53). SP-B null mice and infants with mutations in SFTPB die of respiratory distress after birth. Marked ultrastructural abnormalities are observed in type II epithelial cells in the lungs of SP-B deficient mice, including the lack of lamellar bodies, accumulation of abnormal, large multivesicular bodies (lamellar body precursors), absence of tubular myelin and lack of surfactant activity (52–55).

Hereditary SP-B deficiency
Hereditary SP-B deficiency was first recognized in full-term infants with severe respiratory distress following birth (53). Since that time, more than 75 infants in unrelated families have been identified with this disorder (54). Hereditary SP-B deficiency is an autosomal recessive disease caused by mutations in the SFTPB gene that is located on human chromosome 2. More than 25 distinct mutations, including nonsense, missense and splicing, and termination defects have been identified. Mutations in the SFTPB gene result in either lack of SP-B mRNA or production of abnormal SP-B proproteins that result in misprocessed protein that disturbs synthesis of the active SP-B protein. In addition, SP-B is required for the normal routing and packaging of surfactant lipids and surfactant protein C (SP-C) in type II epithelial cells of the lung (56). Thus, deletion of SP-B also results in the absence of SP-C in the airspaces. While mutations in SP-B generally cause lethal respiratory distress following birth, several patients with partial defects in SP-B synthesis have been associated with severe chronic lung disease in infancy (57–59).

Hereditary SP-B deficiency is a relatively rare, autosomal recessive disorder. The carrier rate for mutations in SFTPB is estimated to be 1 in 600 (60). Mutation in exon 4 (termed the 121 insert) is the most common, being detected in 50–60% of the affected individuals (47). Individuals homozygous for the SFTPB 121 insert, the SFTPB 121 insert inherited in association with other SFTPB mutations, have been identified. While mutations in SFTPB generally cause fatal respiratory distress after birth, haploinsufficiency has not been associated with a recognizable clinical disease in the few number of carriers studied to date (61).

Clinical findings in hereditary SP-B deficiency
Human SP-B deficiency is generally present in full-term infants who develop respiratory distress after birth. Symptoms are generally observed before 12 h of age. History of affected family members and/or consanguinity has been associated with the disorder. Radiographic findings include diffuse alveolar infiltrates, alveolar collapse, reticular–granular infiltrates and air bronchograms in full-term infants without other underlying causes of respiratory failure. In spite of oxygen and assisted ventilation, surfactant replacement and/or extracorporeal membrane oxygenation (ECMO), most infants die in the first week or month of life. Surfactant replacement is not effective; the infants generally have no or transient responses to therapy. Definitive diagnosis is made by identification of mutations in both alleles of the SFTPB gene. Marked histological abnormalities are observed in the lung at autopsy or biopsy, with evidence of diffuse alveolar and bronchiolar damage, atelectasis, hyaline membranes, interstitial thickening, type II cell hyperplasia and accumulation of alveolar macrophages and proteins in the alveoli. The lung pathology in these infants is often categorized as infantile desquamating interstitial pneumonitis (DIP) or congenital pulmonary alveolar proteinosis (Fig. 3). Abnormal accumulation of mutant proSP-B or its processing intermediates have been observed in lungs of patients with mutations in which the abnormal proteins are produced. The absence of SP-B in tracheal aspirates, assessed by ELISA or protein blot, indicates an increased likelihood of the disorder but is not diagnostic. Since SP-B is required for the processing and secretion of SP-C, most mutations in SP-B also cause misprocessing of proSP-C and accumulation of an abnormal proSP-C peptide in the alveoli that can be detected immunohistochemically or by western blot analysis (54,56). Hereditary SP-B deficiency is generally fatal in the neonatal period and no effective therapies have been identified. Some infants have undergone lung transplantation with prolongation and improvement of life (62).



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  		Figure 3. Histopathology of surfactant abnormalities found in the lungs of human patients with mutations in the SFTPB gene (A), mutations in the SFTPC gene (B), mutations in the ABCA3 gene (C) and of control adult lung (D). The histopathologic findings in infants with mutations in the SFTPB, SFTPC and ABCA3 genes (A, B and C, respectively) are remarkably similar, demonstrating varying degrees of interstitial thickening and muscularization of the alveolar septae, remodeling of the alveolar epithelium with type II cell hyperplasia, as well as accumulation of eosinophilic, proteinacous, granular material and alveolar macrophages in the airspaces. All tissue sections were stained with hematoxylin and eosin. All panels are shown at the same magnification. Bar equals 200 µm.

 

   DISORDERS OF THE SP-C GENE (SFTPC)
TOP
 ABSTRACT
 STAGES OF LUNG MORPHOGENESIS
 PULMONARY SURFACTANT IS REQUIRED...
 DISORDERS OF SP-B GENE...
 DISORDERS OF THE SP-C...
DISORDERS OF THE ABCA3...
 SUMMARY
 REFERENCES
 
SP-C is a small hydrophobic protein that plays an important role in surfactant function of lung homeostasis. SP-C was initially isolated from surfactant lipid extracts that were used to treat preterm infants with RDS (63). A single gene encoding SP-C (SFTPC) is located on human chromosome 8. SP-C RNA produces an 191 amino acid proprotein from which an active peptide of 35 amino acids is produced by proteolytic processing in type II epithelial cells of the lung (reviewed in 49,50). The active SP-C is tightly associated with surfactant lipids in the airspaces. ProSP-C is trafficked with proSP-B through the endoplasmic reticulum multivesicular bodies to lamellar bodies within type II epithelial cell. SP-C inserts into phospholipid films and vesicles via an extremely hydrophobic, helical domain. SP-C disrupts acyl group packaging of the lipids, enhances their spreading and recruits lipids to the surface films to confer surfactant-like activity. While SP-B and SP-C interact with lipids via distinct structures, both proteins enhance surfactant activity and are active components of surfactant replacement preparations used clinically.

Hereditary SP-C deficiency
Mutations in the SFTPC gene cause both acute and chronic pulmonary disease in humans. Both lack of SP-C and mutations in the gene encoding SP-C (SFTPC) have been associated with acute and chronic lung disease in infants and adults (49,55,64). A family with severe interstitial lung disease associated with the lack of production of SP-C, as assessed in lung lavage fluid, and by decreased immunostaining for proSP-C in lung biopsies, was identified (65). These findings are consistent with the observation that mice bearing a null allele for the SFTPC gene develop severe interstitial lung disease in the postnatal period (66). Some infants with SFTPC mutations have presented with respiratory failure in the first days of life with clinical findings similar to those associated with SP-B deficiency. Mutations in SFTPC were associated with chronic interstitial lung disease in infants, with histology being variably classified as chronic pneumonitis of infancy, non-specific chronic interstitial pneumonitis and DIP. In adults, the disorder is classified as idiopathic pulmonary fibrosis (IPF), usual interstitial pneumonitis, non-specific interstitial pneumonitis or DIP. While the age of onset, severity of the disease and pathological findings are highly variable, mutations in SFTPC are generally inherited as an autosomal dominant disorder, resulting in severe interstitial lung disease and susceptibility to acute respiratory failure (ARDS) following injury or infection. Variability in histopathologic findings are likely related in part to distinct mutations, age, environmental factors and other genetic modifiers which influence the course of the disease and the pathology observed. SFTPC mutations have been associated with severe pulmonary disease. An extended family bearing a dominantly inherited SFTPC gene was described by Thomas et al. (67) in a kindred of 16 individuals, most of whom developed severe interstitial lung disease. Chronic lung disease caused by SFTPC mutations manifests at various ages from childhood to adulthood. Dyspnea, clubbing, cyanosis, oxygen requirement and pulmonary exacerbations following viral and other infections are common features of the disorder. Pathological findings include alveolar proteinosis, DIP, alveolar thickening, fibrosis and mononuclear infiltration (Fig. 3). Definitive diagnosis is made by identification of mutations in the SFTPC gene. History of dominantly inherited IPF and RDS supports the likelihood of the diagnosis. However, de novo mutations in SFTPC occur. Immunostaining for proSP-C reveals intense staining of proSP-C or proSP-C peptides in type II epithelial cells, likely representing accumulation of misfolded or misprocessed proSP-C (64,67). The abnormal proSP-C protein interferes with the routing and processing of the proSP-C produced from the normal SFTPC allele (68). The pathogenesis of lung disease associated with mutations in SFTPC is not known with clarity. Whether the lack of the active SP-C peptide, proSP-C or cytotoxic effects of the accumulation of mutant proSP-C proteins contribute to the disease remains to be clarified. Definitive therapies for SFTPC mutations have not been developed. Lung transplantation has resulted in improved longevity and quality of life for some individuals with SFTPC mutations.


   DISORDERS OF THE ABCA3 TRANSPORTER
TOP
 ABSTRACT
 STAGES OF LUNG MORPHOGENESIS
 PULMONARY SURFACTANT IS REQUIRED...
 DISORDERS OF SP-B GENE...
 DISORDERS OF THE SP-C...
 DISORDERS OF THE ABCA3...
SUMMARY
 REFERENCES
 
Mutations in the ABCA3 transporter have been recently identified as a cause of acute RDS in term and newborn infants, and the cause of chronic interstitial lung disease in older individuals (69). ABCA3 is a 1704 amino acid, multiple transmembrane protein of the family of ATP-binding cassette (ABC) transporters, of which the cystic fibrosis transmembrane regulator and the multiple drug resistance protein are members. While the precise function of the ABCA3 transporter is unknown, its homologs are involved in lipid transport. ABCA3 is expressed in type II epithelial cells of the lung, being detected at the limiting membranes of lamellar bodies in type II epithelial cells. The structure of the ABCA3 transporter and its localization suggest its potential role in lipid transport to or from the lamellar bodies, suggesting its role in intracellular lipid homeostasis. Lung disease associated with mutations in the ABCA3 gene are inherited in an autosomal recessive manner. History of consanguinity and a family history of fatal neonatal respiratory distress support the likelihood of the disorder. Radiologic findings associated with ABCA3 mutations are consistent with RDS in the newborn infants. Diffuse pulmonary opacification, reticular–granular infiltrates and air bronchograms are observed. Infants are presented with grunting, retractions and cyanosis in the first days of life, and rapidly develop respiratory failure that is refractory to ventilation, surfactant replacement and ECMO. Alveolar proteinosis infiltration by alveolar macrophages, alveolar wall thickening and type II cell hyperplasia has been observed by microscopy at light and electron microscopic levels (Fig. 3). At the electronmicroscopic level, lamellar bodies are abnormally small, supporting the concept that the ABCA3 transporter affects surfactant lipid transport pathways (69). At present, there are no known definitive therapies for lung disease caused by mutations in ABCA3. In spite of intensive care, newborns affected in this disorder generally die from respiratory failure in the neonatal period. Clinical findings and disease progression in older individuals with ABCA3 mutations are not known with certainty.


   SUMMARY
TOP
 ABSTRACT
 STAGES OF LUNG MORPHOGENESIS
 PULMONARY SURFACTANT IS REQUIRED...
 DISORDERS OF SP-B GENE...
 DISORDERS OF THE SP-C...
 DISORDERS OF THE ABCA3...
 SUMMARY
REFERENCES
 
Congenital malformations caused by mutations in genetic pathways regulated by SHH, FGF and TTF-1 cause severe and often lethal respiratory distress following birth (Fig. 4). These genes regulate intracellular signaling and gene transcription that determine formation and differentiation of the respiratory epithelium. Formation of the alveoli and synthesis of pulmonary surfactant by the respiratory epithelium are critical for lung function at birth. Mutations in SFTPB, SFTPC and ABCA3 disrupt surfactant function and cellular homeostasis in the respiratory epithelium, causing either acute respiratory failure or chronic lung disease after birth. Although progress has been made in identifying genes and pathways critical for lung function at birth, the molecular and genetic causes of most lung malformations affecting perinatal lung function remain to be elucidated.



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  		Figure 4. Genetic pathways causing lung malformations and dysfunction. SHH, FGF and TTF-1 dependent pathways play central roles in lung morphogenesis. Mutations or deletion of genes in these pathways disrupt tracheal–esophageal separation and alter branching morphogenesis. TTF-1 regulates the differentiation of the lung epithelium and the expression of proteins required for surfactant homeostasis in the alveolar type II cells, including SP-B and SP-C. Mutations in SFTPB, SFTPC and ABCA3 disrupt production of the proteins in alveolar type II cells, leading to surfactant deficiency and respiratory failure in the newborn period.

 

   ACKNOWLEDGEMENTS
 
The authors wish to thank Ann Maher and Elan Gada for assistance with the manuscript. This work was supported by NIH grants HL38859 (J.A.W.), SCOR HL56387 (J.A.W., S.E.W., B.C.T.), HL60549 (B.C.T.), HL71832 (B.C.T.) and U54 RR19498 (B.C.T.).


   FOOTNOTES
 
* To whom correspondence should be addressed at: Division of Pulmonary Biology, Cincinnati Children's Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, OH 45229-3039, USA. Tel: +1 5136364830; Fax: +1 5136367868; Email: jeff.whitsett{at}cchmc.org


   REFERENCES
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 ABSTRACT
 STAGES OF LUNG MORPHOGENESIS
 PULMONARY SURFACTANT IS REQUIRED...
 DISORDERS OF SP-B GENE...
 DISORDERS OF THE SP-C...
 DISORDERS OF THE ABCA3...
 SUMMARY
 REFERENCES
 

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