A Novel Mutation (c.705C>A (p.C235*) (p.Cys235Ter)) in the SFTPB Gene That Causes Severe Respiratory Failure in A Term Newborn (original) (raw)
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The importance of surfactant on the development of neonatal pulmonary diseases
Clinics, 2007
Pulmonary surfactant is a substance composed of a lipoprotein complex that is essential to pulmonary function. Pulmonary surfactant proteins play an important role in the structure, function, and metabolism of surfactant; 4 specific surfactant proteins have been identified: surfactant proteins-A, surfactant proteins-B, surfactant proteins-C, and surfactant proteins-D. Clinical, epidemiological, and biochemical evidence suggests that the etiology of respiratory distress syndrome is multifactorial with a significant genetic component. There are reports about polymorphisms and mutations on the surfactant protein genes, especially surfactant proteins-B, that may be associated with respiratory distress syndrome, acute respiratory distress syndrome, and congenital alveolar proteinosis. Individual differences regarding respiratory distress syndrome and acute respiratory distress syndrome as well as patient response to therapy might reflect phenotypic diversity due to genetic variation, in part. The study of the differences between the allelic variants of the surfactant protein genes can contribute to the understanding of individual susceptibility to the development of several pulmonary diseases. The identification of the polymorphisms and mutations that are indeed important for the pathogenesis of the diseases related to surfactant protein dysfunction, leading to the possibility of genotyping individuals at increased risk, constitutes a new research field. In the future, findings in these endeavors may enable more effective genetic counseling as well as the development of prophylactic and therapeutic strategies that would provide a real impact on the management of newborns with respiratory distress syndrome and other pulmonary diseases.
Hum Mut, 1999
Several human respiratory disorders have been linked to an abnormality of pulmonary surfactant synthesis or turnover. Among those conditions, hereditary deficiency in the hydrophobic surfactant protein B (SP-B) has been recognized as a rare cause of respiratory failure in term newborn infants. Homozygosity for a common mutation (1549C®GAA, or 121ins2) of the SP-B-encoding gene (SFTPB) results in rapidly fatal respiratory failure, with complete absence of the mRNA and protein observed in lung fluid or biopsy specimens. Hereditary SP-B deficiency is also associated with aberrant processing of proSP-C and deficiency of the active SP-C peptide. In the present study, we characterized the SFTPB gene in an infant with severe unexplained respiratory distress and identified a paternally derived 1549C®GAA lesion, as well as a hitherto unreported mutation (457delC) inherited from the mother. Analysis of bronchoalveolar lavage fluid demonstrated the complete absence of SP-B. However, unlike previous infants with hereditary SP-B deficiency, proSP-C was processed to the active SP-C peptide, suggesting that the defect in SP-B, rather than SP-C, caused the respiratory distress in this infant. The present findings demonstrate the importance of SFTPB in pulmonary function and support the need for further genotype-phenotype correlations in patients with SP-B deficiency. Hum Mutat 14:502-509, 1999.
Neonatal respiratory failure due to a novel mutation in the surfactant protein C gene
Journal of Perinatology, 2010
A full-term infant developed respiratory distress immediately after birth, requiring a prolonged course of extra-corporeal membrane oxygenation, followed by high-frequency ventilation. She was unable to wean off mechanical ventilation, required tracheostomy, and ultimately lung transplantation. A novel mutation in the surfactant C protein gene was identified as the cause of her lung disease.
Molecular Genetics and Metabolism, 2009
Pulmonary surfactant is a complex mixture of phospholipids (PL) and proteins (SP) that reduce surface tension at the air-liquid interface of the alveolus. It is made up of about 70% to 80% PL, mainly dipalmitoylphosphatidylcholine (DPPC), 10% SPA , B, C and D, and 10% neutral lipids, mainly cholesterol. Surfactant is synthesized, assembled, transported and secreted into the alveolus where it is degraded and then recycled. Metabolism of surfactant is slower in newborns, especially preterm, than in adults. Defective pulmonary surfactant metabolism results in respiratory distress with attendant morbidity and mortality. This occurs due to accelerated breakdown by oxidation, proteolytic degradation, inhibition or inherited defects of surfactant metabolism. Prenatal corticosteroids, surfactant replacement, whole lung lavage and lung transplantation have yielded results in managing some of these defects. Gene therapy could prove valuable in treating inherited defects of surfactant metabolism.
A major deletion in the surfactant protein-B gene causing lethal respiratory distress
Acta Paediatrica, 2007
Background: Loss of function mutations in the surfactant protein-B gene (SFTPB) cause lethal neonatal respiratory distress due to reduced or absent expression of mature surfactant protein B (SP-B, encoded in exons 6 and 7). No large deletions in SFTPB have been previously identified.Aim: Genomic, proteomic and immunohistochemical characterization of a 3 kb deletion in SFTPB.Methods: A full-term newborn presented with refractory respiratory failure. We amplified and sequenced SFTPB from the infant and both parents, determined SP-B protein expression in tracheal aspirate samples using Western-blot analysis, and performed immunohistochemical staining and electron microscopy of lung biopsy tissue.Results: The infant was homozygous for a 2958 bp deletion in SFTPB that included exons 7 and 8. Both asymptomatic parents were heterozygous for the deletion. A truncated mature SP-B peptide was detected on Western blotting of tracheal aspirate. Amino acid sequence specific to that encoded in exon 5 was present, but that encoded by exon 7 was absent. ProSP-B expression was robust within alveolar type II cells and lamellar body structure was disrupted.Conclusions: This deletion in SFTPB resulted in SP-B deficiency due to absence of elements in mature SP-B that are critical for appropriate peptide folding, trafficking and processing.
Two Mutations in Surfactant Protein C Gene Associated with Neonatal Respiratory Distress
Case Reports in Pediatrics, 2015
Multiple mutations of surfactant genes causing surfactant dysfunction have been described. Surfactant protein C (SP-C) deficiency is associated with variable clinical manifestations ranging from neonatal respiratory distress syndrome to lethal lung disease. We present an extremely low birth weight male infant with an unusual course of respiratory distress syndrome associated with two mutations in the SFTPC gene: C43-7G>A and 12T>A. He required mechanical ventilation for 26 days and was treated with 5 subsequent doses of surfactant with temporary and short-term efficacy. He was discharged at 37 weeks of postconceptional age without any respiratory support. During the first 16 months of life he developed five respiratory infections that did not require hospitalization. Conclusion. This mild course in our patient with two mutations is peculiar because the outcome in patients with a single SFTPC mutation is usually poor.
Mutations of the Surfactant Protein C (SPC) gene (SFTPC) have been associated with childhood interstitial lung disease (chILD) with variable age of onset, severity of lung disease, and outcomes. We report a novel mutation in SFTPC [c.435G->A, p.(Gln145)] that was associated with onset of symptoms in early infancy, progressive respiratory failure with need for prolonged mechanical ventilatory support, and eventual lung transplant at 1 year of age. While the mutation was not predicted to alter the amino acid sequence of the SP-C precursor protein, analysis of SP-C transcripts demonstrated skipping of exon 4. Because of limited data about the outcomes of infants with SFTPC mutations, we conducted a systematic review of all the SFTPC mutations reported in the literature in order to define their presenting features, clinical and radiologic features, and outcomes. Further advances in our understanding of chILD and creation of an international registry will help to track these patients and their outcomes. Pediatr Pulmonol. 2016; 9999:XX–XX. ß 2016 Wiley Periodicals, Inc.
Journal of Perinatology, 2017
ObjectiveGenetic surfactant dysfunction causes respiratory failure in term and near-term newborn infants, but little is known of such condition in prematures. We evaluated genetic surfactant dysfunction in premature newborn infants with severe RDS.Patients and methodsA total of 68 preterm newborn infants with gestational age ≤32 weeks affected by unusually severe RDS were analysed for mutations in SFTPB, SFTPC and ABCA3. Therapies included oxygen supplementation, nasal CPAP, different modalities of ventilatory support, administration of exogenous surfactant, inhaled nitric oxide and steroids. Molecular analyses were performed on genomic DNA extracted from peripheral blood and Sanger sequencing of whole gene coding regions and intron junctions. In one case histology and electron microscopy on lung tissue was performed.ResultsHeterozygous previously described rare or novel variants in surfactant proteins genes ABCA3, SFTPB and SFTPC were identified in 24 newborn infants. In total, 11 infants died at age of 2 to 6 months. Ultrastructural analysis of lung tissue of one infant showed features suggesting ABCA3 dysfunction.DiscussionRare or novel genetic variants in genes encoding surfactant proteins were identified in a large proportion (35%) of premature newborn infants with particularly severe RDS. We speculate that interaction of developmental immaturity of surfactant production in association with abnormalities of surfactant metabolism of genetic origin may have a synergic worsening phenotypic effect.