Compound SFTPB 1549C>GAA (121ins2) and 457delC Heterozygosity in Severe Congenital Lung Disease and Surfactant Protein B (SP-B) Deficiency (original) (raw)
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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.
2021
Surfactants are surface-active agents lowering surface tension in the airways of the lung. It plays an important role on pulmonary function. Surfactant proteins constitute 10 percent of the surfactant molecule. Mutations in genes encoding surfactant proteins can be fatal. Surfactant protein B (SFTPB) gene mutation accounts for 50 percent of the cases that underwent lung transplantation for the treatment of severe respiratory failure due to surfactant protein gene mutations in infancy. More than 100 mutations in the surfactant protein B gene have been described. Variants in SPTPB cause pulmonary disease and due to production of insufficient amount and/or functionally abnormal surfactant, resulting in restrictive pathophysiology, with lungs that are poorly compliant and prone to atelectasis and low lung volumes. Here, we present a case of a term newborn who was referred with the diagnosis of persistent pulmonary hypertension of the newborn, who died due to a previously unidentified su...
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.
Clin Chem Lab Med, 2001
Pulmonary surfactant is a multimolecular complex located at the air-water interface within the alveolus to which a range of physical (surface-active propert i e s ) and immune functions has been assigned. This complex consists of a surface-active lipid layer (consisting mainly of phospholipids), and of an aqueous subphase. From discrete surfactant sub-fractions one can isolate strongly hydrophobic surfactant proteins B (SP-B) and C (SP-C) as well as collectins SP-A and SP-D, which were shown to have specific structural, metabolic, or immune properties. Inborn or acquired abnormalities of the s u rfactant, qualitative or quantitative in nature, account for a number of human diseases. Beside hyaline membrane disease of the preterm neonate, a cluster of hereditary or acquired lung diseases has been characterized by periodic acid-Schiff-positive material filling the alveoli. From this heterogeneous nosologic group, at least two discrete entities presently emerge. The first is the SP-B deficiency, in which an essentially proteinaceous material is stored within the alveoli, and which represents an autosomal recessive Mendelian entity linked to the S F T P B gene (MIM 1786640). The disease usually generally entails neonatal respiratory distress with rapid fatal outcome, although partial or transient deficiencies have also been observed. The second is alveolar proteinosis, characterized by the storage of a mixed protein and lipid material, which constitutes a relatively heterogeneous clinical and biological syndrome, especially with regard to age at onset (from the neonate through to adulthood) as well as the severity of associated signs. Murine models, with a targeted mutation of the gene encoding granulocyte macrophage colonystimulating factor (GM-CSF) (C s f g m) or the  subunit of its receptor (I l 3 r b 1) support the hypothesis of an abnormality of surfactant turnover in which the alveolar macrophage is a key player. Apart from SP-B deficiency, in which a near-consensus diagnostic chart can be designed, the ascertainment of other abnormalities of surfactant metabolism is not straightforward. The disent-anglement of this disease cluster is however essential to propose specific therapeutic procedures: repeated broncho-alveolar lavages, GM-CSF replacement, bone marrow grafting or lung transplantation.
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.
Genetic surfactant dysfunction in newborn infants and children with acute and chronic lung disease
2017
Mutations in genes encoding surfactant protein B (SP-B), ATP-binding cassette transporter A3 (ABCA3) and surfactant protein C (SP-C) can result in neonatal and pediatric lung disease. We retrospectively reviewed 391 molecular analyses of genes encoding SP-B ( SFTPB ), SP-C ( SFTPC ) and ABCA3 ( ABCA3 ) performed in our laboratory from 2000 to 2015 in term and preterm newborn infants with severe respiratory distress syndrome (RDS), infants and children with interstitial lung disease (ILD), chorionic villi for prenatal diagnosis, parents and siblings of affected infants. Direct sequencing of SFTPB , SFTPC and ABCA3 was performed on genomic DNA extracted from peripheral blood. Histopathologic, immunohistochemical and ultrastructural analyses were performed when lung tissue was available. Genetic variants in SFTPB , SFTPC , ABCA3 were identified in 71 of 181 (39%) term and preterm newborn infants tested for severe and unexplained RDS and in 38 of 74 (51%) infants and children with ILD. ...
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.