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Lawrence M Nogee

Publications and source records attributed to Lawrence M Nogee.

17 recordsLinked to original sources
PubMed2006

Surfactant composition and function in patients with ABCA3 mutations.

Mutations in the gene encoding the ATP binding cassette transporter member A3 (ABCA3) are associated with fatal surfactant deficiency. ABCA3 lines the limiting membrane of lamellar bodies within alveolar type-II cells, suggesting a role in surfactant metabolism. The objective of this study was to determine the surfactant phospholipid composition and function in patients with mutations in the ABCA3 gene. Bronchoalveolar lavage (BAL) fluid was analyzed from three groups of infants: 1) Infants with ABCA3 mutations, 2) infants with inherited surfactant protein-B deficiency (SP-B), and 3) patients without parenchymal lung disease (CON). Surfactant phospholipid profile was determined using two-dimensional thin-layer chromatography, and surface tension was measured with a pulsating bubble surfactometer. Phosphatidylcholine comprised 41 +/- 19% of the total phospholipid in the BAL fluid of the ABCA3 group compared with 78 +/- 3% and 68 +/- 18%, p = 0.008 and 0.05, of the CON and SP-B groups, respectively. Surface tension was 31.5 +/- 9.3 mN/m and was significantly greater than CON but no different from SP-B. We conclude that mutations in ABCA3 are associated with surfactant that is deficient in phosphatidylcholine and has decreased function, suggesting that ABCA3 plays an important role in pulmonary surfactant phospholipid homeostasis.

ATP-Binding Cassette Transporters↗
PubMed2006

Long-term outcomes after infant lung transplantation for surfactant protein B deficiency related to other causes of respiratory failure.

OBJECTIVE: To determine if the outcomes of lung transplantation for infants with surfactant protein-B (SP-B) deficiency are unique. STUDY DESIGN: From a prospective analysis to identify infants with genetic causes of surfactant deficiency, we identified 33 SP-B-deficient infants from 1993 to 2005, and, among those undergoing lung transplantation (n = 13), compared their survival, pulmonary function, and developmental progress with infants who underwent transplantation at <1 year of age for parenchymal lung disease (n = 13) or pulmonary vascular disease (n = 11). RESULTS: Five-year survival rates ( approximately 50%, P = .3) and causes of death were similar for all three groups once the infants underwent transplantation. However, significant pretransplantation mortality decreased 5-year survival from listing to approximately 30% (P = .17). Pulmonary function, development of bronchiolitis obliterans, and school readiness were similar among the three groups. We detected anti SP-B antibody in serum of 3 of 7 SP-B-deficient infants and none of 7 SP-B-sufficient infants but could not identify any associated adverse outcomes. CONCLUSIONS: Long-term outcomes after infant lung transplantation for SP-B-deficient infants are similar to those of infants transplanted for other indications. These outcomes are important considerations in deciding to pursue lung transplantation for infants with disorders of alveolar homeostasis.

Female↗
PubMed2006

Defects in surfactant synthesis: clinical implications.

Since the original description of deficiency of the pulmonary surfactant in premature newborn infants by Avery and Mead in 1959, respiratory distress syndrome has most commonly been attributed to developmental immaturity of surfactant production. Studies of different ethnic groups, gender, targeted gene ablation in murine lineages, and recent clinical reports of monogenic causes of neonatal respiratory distress syndrome have demonstrated that genetic defects disrupt pulmonary surfactant metabolism and cause respiratory distress syndrome, especially in term or near-term infants and in older infants, children, and adults. In contrast to developmental causes of respiratory distress, which may improve as infants and children mature, genetic causes result in both acute and chronic (and potentially irreversible) respiratory failure.

Humans↗
PubMed2006

ABCA3 deficiency: neonatal respiratory failure and interstitial lung disease.

ABCA3 is a member of the ATP Binding Cassette family of proteins, transporters that hydrolyze ATP in order to move substrates across biological membranes. Mutations in the gene encoding ABCA3 have been found in children with severe neonatal respiratory disease and older children with some forms of interstitial lung disease. This review summarizes current knowledge concerning clinical, genetic, and pathologic features of the lung disease associated with mutations in the ABCA3 gene, and also briefly reviews some other forms of childhood interstitial lung diseases that have their antecedents in the neonatal period and may also have a genetic basis.

ATP-Binding Cassette Transporters↗
PubMed2006

Genetically engineered mice in understanding the basis of neonatal lung disease.

Advances in genetic engineering have allowed the creation of animals with additional or deleted genes. New genes may be inserted in mice, specific genes inactivated or "knocked out," and more complex animals created in which genes can be turned on or off at different times in development or in different tissues. These animal models allow for more detailed studies of the proteins encoded by the manipulated gene, an improved understanding of the pathophysiology of diseases resulting from the genetic alterations, and model organisms in which to study potential new therapies. Multiple mouse models involving genes important in surfactant production and regulation relevant to lung disease observed in human newborns have been created. This review will discuss the creation of such animals and illustrate their utility in understanding human disease.

Animals↗
PubMed2006

Genetics of pediatric interstitial lung disease.

PURPOSE OF REVIEW: The interstitial lung diseases are a heterogeneous group of rare disorders of largely unknown etiology. The occurrence of familial cases of pediatric interstitial lung diseases with the onset of symptoms developing early in infancy has suggested a genetic basis for some forms of interstitial lung diseases in children. RECENT FINDINGS: Mutations in the genes encoding surfactant protein C, SFTPC, and a member of the adenosine triphosphate-binding cassette family of proteins, ABCA3, have been shown to result in pediatric interstitial lung diseases inherited in autosomal-dominant and autosomal-recessive patterns, respectively. There is overlap in both the clinical and histopathologic features of these disorders. SUMMARY: Identification of genes responsible for pediatric interstitial lung diseases provides the opportunity for noninvasive testing to establish an etiologic diagnosis, to counsel family members for their recurrence risk, and to classify these rare disorders more accurately. A better understanding of the cause and pathophysiology of these disorders may provide additional insights into the causes of other forms of pediatric interstitial lung diseases, and may suggest novel treatment approaches.

ATP-Binding Cassette Transporters↗
PubMed2005

ABCA3 mutations associated with pediatric interstitial lung disease.

RATIONALE: ABCA3 is a member of the ATP-binding cassette family of proteins that mediate the translocation of a wide variety of substrates, including lipids, across cellular membranes. Mutations in the gene encoding ABCA3 were recently identified in full-term neonates with fatal surfactant deficiency. OBJECTIVE: To test the hypothesis that ABCA3 mutations are not always associated with fatal neonatal lung disease but are a cause of pediatric interstitial lung disease. METHODS: DNA samples were obtained from 195 children with chronic lung disease of unknown etiology. The 30 coding exons of the ABCA3 gene were sequenced in four unrelated children with a referring diagnosis of desquamative interstitial pneumonitis and who were older than 10 years at the time of enrollment. RESULTS: Three of four patients (ages 16, 23, and 11 years) with desquamative interstitial pneumonitis had ABCA3 mutations identified on both alleles. All three had the same missense mutation (E292V) and a second unique mutation. The E292V mutation was not found on 200 control alleles from adults without lung disease, but seven additional patients of the remaining study patients had the E292V mutation on one allele. Immunohistochemical analysis of surfactant protein expression in three patients revealed a specific staining pattern for surfactant protein-B, which was the same pattern observed in several infants with fatal lung disease due to ABCA3 mutations. CONCLUSION: ABCA3 mutations cause some types of interstitial lung disease in pediatric patients.

ATP-Binding Cassette Transporters↗
PubMed2005

A common mutation in the surfactant protein C gene associated with lung disease.

OBJECTIVE: To determine the contribution of the surfactant protein C (SP-C) I73T mutation to lung disease. STUDY DESIGN: Genomic DNA was obtained from 116 children with interstitial lung disease (ILD) or chronic lung disease of unclear cause and from 166 control subjects and was screened for the I73T mutation using an allele-specific polymerase chain reaction assay. RESULTS: The I73T mutation was found on 7 of 232 SP-C alleles from 7 unrelated children with ILD but was not found on 332 control SP-C alleles ( P < .01, Fisher exact test). The I73T mutation segregated with lung disease in one kindred with familial ILD. The I73T mutation was found in an asymptomatic parent from two different families with affected children consistent with variable penetrance, but it was not found in either asymptomatic parent of two other unrelated affected children consistent with a de novo mutation. Analysis of single nucleotide polymorphisms indicated diverse genetic backgrounds of the I73T alleles. Immunohistochemical analysis of lung tissue from an infant with the I73T mutation demonstrated normal staining patterns for proSP-B, SP-B, and proSP-C. CONCLUSIONS: These findings support the hypothesis that the I73T mutation predisposes to or causes lung disease.

Alleles↗
PubMed2004

Genetic mechanisms of surfactant deficiency.

The production of pulmonary surfactant is necessary to maintain alveolar stability and normal lung function. Mutations in three different genes important for surfactant production and function have now been recognized to result in surfactant deficiency and acute and/or chronic lung disease. The clinical and laboratory features associated with these genetic disorders, along with their implications for the understanding of normal surfactant metabolism, are reviewed.

ATP-Binding Cassette Transporters↗
PubMed2004

N-terminally extended surfactant protein (SP) C isolated from SP-B-deficient children has reduced surface activity and inhibited lipopolysaccharide binding.

In both humans and mice, a deficiency of surfactant protein B (SP-B) is associated with a decreased concentration of mature SP-C and accumulation of a larger SP-C peptide, denoted SP-C(i), which is not observed under normal conditions. Isolation of hydrophobic polypeptides from the lungs of children who died with two different SP-B mutations yielded pure SP-C(i) and showed only trace amounts of mature SP-C. Determination of the SP-C(i) covalent structure revealed a 12-residue N-terminal peptide segment, followed by a 35-residue segment that is identical to mature SP-C. The SP-C(i) structure determined herein is similar to that of a proposed late intermediate in the processing of proSP-C, suggesting that SP-C(i) is the immediate precursor of SP-C. In bronchoalveolar lavage fluid from transgenic mice with a focal deficiency of SP-B, SP-C(i) was detected in the biophysically active, large aggregate fraction and was associated with membrane structures that are typical for a large aggregate surfactant. However, unlike SP-C, SP-C(i) exhibited a very poor ability to promote phospholipid adsorption, gave high surface tension during cyclic film compression, and did not bind lipopolysaccharide in vitro. SP-C(i) is thus capable of associating with surfactant lipids, but its N-terminal dodecapeptide segment must be proteolytically removed to generate a biologically functional peptide. The results of this study indicate that the early postnatal fatal respiratory distress seen in SP-B-deficient children is combined with the near absence of active variants of SP-C.

Amino Acid Sequence↗
PubMed2004

ABCA3 gene mutations in newborns with fatal surfactant deficiency.

BACKGROUND: Pulmonary surfactant forms a lipid-rich monolayer that coats the airways of the lung and is essential for proper inflation and function of the lung. Surfactant is produced by alveolar type II cells, stored intracellularly in organelles known as lamellar bodies, and secreted by exocytosis. The gene for ATP-binding cassette transporter A3 (ABCA3) is expressed in alveolar type II cells, and the protein is localized to lamellar bodies, suggesting that it has an important role in surfactant metabolism. METHODS: We sequenced each of the coding exons of the ABCA3 gene in blood DNA from 21 racially and ethnically diverse infants with severe neonatal surfactant deficiency for which the etiologic process was unknown. Lung tissue from four patients was examined by high-resolution light and electron microscopy. RESULTS: Nonsense and frameshift mutations, as well as mutations in highly conserved residues and in splice sites of the ABCA3 gene were identified in 16 of the 21 patients (76 percent). In five consanguineous families with mutations, each pair of siblings was homozygous for the same mutation and each mutation was found in only one family. Markedly abnormal lamellar bodies were observed by ultrastructural examination of lung tissue from four patients with different ABCA3 mutations, including nonsense, splice-site, and missense mutations. CONCLUSIONS: Mutation of the ABCA3 gene causes fatal surfactant deficiency in newborns. ABCA3 is critical for the proper formation of lamellar bodies and surfactant function and may also be important for lung function in other pulmonary diseases. Since it is closely related to ABCA1 and ABCA4, proteins that transport phospholipids in macrophages and photoreceptor cells, it may have a role in surfactant phospholipid metabolism.

ATP-Binding Cassette Transporters↗
PubMed2004

Informed consent for genetic research.

BACKGROUND: Rapid technological advances in genetic research and public concern about genetic discrimination have led to anticipatory safeguards in the informed consent process in the absence of legal examples of proven discrimination. Despite federal and state regulations to restrict access to personal health information, including genetic information, institutional review boards have required the addition of language to informed consent documents that warns about the risks of discrimination with participation in genetic research. OBJECTIVE: To determine the reasons that families refused consent for their infant's participation in a study evaluating a genetic cause of respiratory distress syndrome. DESIGN: Survey conducted between February 1, 2002, and March 31, 2003. SETTING: Academic, tertiary free-standing children's hospital. PARTICIPANTS: A convenience sample of 465 families were approached for consent. The 135 families who refused consent were surveyed. MAIN OUTCOME MEASURES: Reasons for refusal. RESULTS: Of the nonconsenting families, 79% spontaneously and specifically identified institutionally required language in our consent form concerning the risk of denial of access to health insurance and employment as the primary reason for refusal; 97% indicated that their fears resulted directly from language in our consent form. Only 20% of families who refused consent cited inadequate time to consider the study. CONCLUSIONS: The institutionally required description of risk of genetic discrimination due solely to participation in genetic research was the primary reason for refusal to consent in this cohort. Information about federally and institutionally mandated protections for confidentiality of participants in genetic research should be included in the informed consent document to balance the description of hypothetical risks and more accurately inform subjects.

Employment↗
PubMed2004

Alterations in SP-B and SP-C expression in neonatal lung disease.

The hydrophobic surfactant proteins, SP-B and SP-C, have important roles in surfactant function. The importance of these proteins in normal lung function is highlighted by the lung diseases associated with abnormalities in their expression. Mutations in the gene encoding SP-B result in severe, fatal neonatal lung disease, and mutations in the gene encoding SP-C are associated with chronic interstitial lung diseases in newborns, older children, and adults. This work reviews the current state of knowledge concerning the lung diseases associated with mutations in the SP-B and SP-C genes, and the potential roles of abnormal SP-B and SP-C expression and genetic variation in these genes in other lung diseases.

Humans↗
PubMed2003

Progressive lung disease and surfactant dysfunction with a deletion in surfactant protein C gene.

Mutations in the surfactant protein (SP)-C gene are responsible for familial and sporadic interstitial lung disease (ILD). The consequences of such mutations on pulmonary surfactant composition and function are poorly understood. To determine the effects of a mutation in the SP-C gene on surfactant, we obtained lung tissue at the time of transplantation from a 14-mo-old infant with progressive ILD. An in-frame 9-bp deletion spanning codons 91-93 in Exon 3 of the SP-C gene was present on one allele; neither parent carried this deletion. SP-C mRNA was present in normal size and amount. By immunofluorescence, proSP-C was aggregated within alveolar Type II cells in a compartment separate from SP-B. In airway surfactant, there was little or no mature SP-B or SP-C; SP-A content was increased. Minimum surface tension was increased (20 mN/m, normal < 5 mN/m). Type II cells contained normal and disorganized appearing lamellar bodies by electron microscopy. This spontaneous deletion on one allele of the SP-C gene was associated with sporadic ILD and abnormalities in surfactant composition and function. We propose that a dominant negative effect on surfactant protein metabolism and function results from aggregation of misfolded proSP-C and subsequent cell injury and inflammation.

Adult↗
PubMed2003

Expression of a human surfactant protein C mutation associated with interstitial lung disease disrupts lung development in transgenic mice.

Surfactant Protein C (SP-C) is a secreted transmembrane protein that is exclusively expressed by alveolar type II epithelial cells of the lung. SP-C associates with surfactant lipids to reduce surface tension within the alveolus, maintaining lung volume at end expiration. Mutations in the gene encoding SP-C (SFTPC) have recently been linked to chronic lung disease in children and adults. The goal of this study was to determine whether a disease-linked mutation in SFTPC causes lung disease in transgenic mice. The SFTPC mutation, designated g.1728 G --> A, results in the deletion of exon4, generating a truncated form of SP-C (SP-C(Deltaexon4)). cDNA encoding SP-C(Deltaexon4) was constitutively expressed in type II epithelial cells of transgenic mice. Viable F0 transgene-positive mice were not generated after two separate rounds of pronuclear injections. Histological analysis of lung tissue harvested from embryonic day 17.5 F0 transgene-positive fetuses revealed that SP-C(Deltaexon4) caused a dose-dependent disruption in branching morphogenesis of the lung associated with epithelial cell cytotoxicity. Transient expression of SP-C(Deltaexon4) in isolated type II epithelial cells or HEK293 cells resulted in incomplete processing of the mutant proprotein, a dose-dependent increase in BiP transcription, trapping of the proprotein in the endoplasmic reticulum, and rapid degradation via a proteasome-dependent pathway. Taken together, these data suggest that the g.1728 G --> A mutation causes misfolding of the SP-C proprotein with subsequent induction of the unfolded protein response and endoplasmic reticulum-associated degradation pathways ultimately resulting in disrupted lung morphogenesis.

Animals↗