Altered surfactant homeostasis and recurrent respiratory failure secondary to TTF-1 nuclear targeting defectReport as inadecuate

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Respiratory Research

, 12:115

First Online: 01 December 2011Received: 08 April 2011Accepted: 25 August 2011


BackgroundMutations 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.

MethodsThe 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 H2O and C-leucine; fractional synthetic rate was derived from gas chromatography-mass spectrometry H and C enrichment curves. Six intubated infants with no primary lung disease were used as controls.

ResultsLung 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.

ConclusionDefective 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.

Keywordsthyroid transcription factor 1 ATP binding cassette transporters lung diseases, interstitial pulmonary surfactants pituitary insufficiency pulmonary surfactant-associated protein B lung-brain-thyroid syndrome AbbreviationsSFTPBsurfactant protein-B gene

SP-Bsurfactant protein-B

ABCA3adenosine triphosphate-binding cassette transporter A3

SFTPCsurfactant protein-C gene

SP-Csurfactant protein-C

TTF-1thyroid transcription factor-1

NKX2.1NK2 homeobox-1

T-EBPthyroid-specific enhancer-bnding protein

RDSrespiratory distress syndrome

iNOinhaled nitric oxide

FT4free thyroxin

FT3free triiodothyronine

TSHthyroid-stimulating hormone

GHgrowth hormone

ACTHadrenocorticotropic hormone

aCGHarray chromatine genomic hybridization


MTMasson trichrome

PASperiodic acid Schiff

proSP-Bsurfactant apoprotein-B

proSP-Csurfactant apoprotein-C

TGF-β1transforming growth factor-β1

TAtracheal aspirate

DSPCdisaturated phophatidylcholine


GCgas chromatography

IRMSisotope ratio-mass spectrometry

MSmass spectrometry.

Electronic supplementary materialThe online version of this article doi:10.1186-1465-9921-12-115 contains supplementary material, which is available to authorized users.

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Author: Donatella Peca - Stefania Petrini - Chryssoula Tzialla - Renata Boldrini - Francesco Morini - Mauro Stronati - Virgilio P 


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