Altered surfactant homeostasis and recurrent respiratory failure secondary to TTF-1 nuclear targeting defect

Respiratory Research

Olivier Danhaive⁴  Paola E Cogo¹  Virgilio P Carnielli⁵  Mauro Stronati³  Francesco Morini⁴  Renata Boldrini⁶  Chryssoula Tzialla³  Stefania Petrini²  Donatella Peca⁴ 

[1] Pediatric Cardiosurgical Intensive Care Unit, Bambino Gesù Children's Hospital IRCCS, Rome, Italy;Research Center, Bambino Gesù Children's Hospital IRCCS, Rome, Italy;Division of Neonatology, Fondazione-IRCCS Policlinico San Matteo, Pavia, Italy;Department of Medical and Surgical Neonatology, Bambino Gesù Children's Hospital IRCCS, Rome, Italy;Neonatal Division, Institute of Maternal-Infantile Sciences, Polytechnic University of Marche, Azienda Ospedaliera Universitaria Ospedali Riuniti Ancona, Italy;Division of Clinical Pathology, Bambino Gesù Children's Hospital IRCCS, Rome, Italy

关键词: lung-brain-thyroid syndrome;    pulmonary surfactant-associated protein B;    pituitary insufficiency;    pulmonary surfactants;    lung diseases, interstitial;    ATP binding cassette transporters;    thyroid transcription factor 1;   

Others  :  796807
DOI  :  10.1186/1465-9921-12-115

 received in 2011-04-08, accepted in 2011-08-25,  发布年份 2011

【 摘 要 】

Background

Mutations of genes affecting surfactant homeostasis, such as SFTPB, SFTPC and ABCA3, lead to diffuse lung disease in neonates and children. Haploinsufficiency of NKX2.1, the gene encoding the thyroid transcription factor-1 (TTF-1) - critical for lung, thyroid and central nervous system morphogenesis and function - causes a rare form of progressive respiratory failure designated brain-lung-thyroid syndrome. Molecular mechanisms involved in this syndrome are heterogeneous and poorly explored. We report a novel TTF-1 molecular defect causing recurrent respiratory failure episodes in an infant.

Methods

The subject was an infant with severe neonatal respiratory distress syndrome followed by recurrent respiratory failure episodes, hypopituitarism and neurological abnormalities. Lung histology and ultrastructure were assessed by surgical biopsy. Surfactant-related genes were studied by direct genomic DNA sequencing and array chromatine genomic hybridization (aCGH). Surfactant protein expression in lung tissue was analyzed by confocal immunofluorescence microscopy. For kinetics studies, surfactant protein B and disaturated phosphatidylcholine (DSPC) were isolated from serial tracheal aspirates after intravenous administration of stable isotope-labeled ²H₂O and ¹³C-leucine; fractional synthetic rate was derived from gas chromatography/mass spectrometry ²H and ¹³C enrichment curves. Six intubated infants with no primary lung disease were used as controls.

Results

Lung biopsy showed desquamative interstitial pneumonitis and lamellar body abnormalities suggestive of genetic surfactant deficiency. Genetic studies identified a heterozygous ABCA3 mutation, L941P, previously unreported. No SFTPB, SFTPC or NKX2.1 mutations or deletions were found. However, immunofluorescence studies showed TTF-1 prevalently expressed in type II cell cytoplasm instead of nucleus, indicating defective nuclear targeting. This pattern has not been reported in human and was not found in two healthy controls and in five ABCA3 mutation carriers. Kinetic studies demonstrated a marked reduction of SP-B synthesis (43.2 vs. 76.5 ± 24.8%/day); conversely, DSPC synthesis was higher (12.4 vs. 6.3 ± 0.5%/day) compared to controls, although there was a marked reduction of DSPC content in tracheal aspirates (29.8 vs. 56.1 ± 12.4% of total phospholipid content).

Conclusion

Defective TTF-1 signaling may result in profound surfactant homeostasis disruption and neonatal/pediatric diffuse lung disease. Heterozygous ABCA3 missense mutations may act as disease modifiers in other genetic surfactant defects.

【 授权许可】

   
2011 Peca et al; licensee BioMed Central Ltd.

【 图 表 】

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