title: NKX2-1 mutations leading to surfactant protein promoter dysregulation cause interstitial lung disease in "Brain-Lung-Thyroid Syndrome".
abstract: NKX2-1 (NK2 homeobox 1) is a critical regulator of transcription for the surfactant protein (SP)-B and -C genes (SFTPB and SFTPC, respectively). We identified and functionally characterized two new de novo NKX2-1 mutations c.493C>T (p.R165W) and c.786_787del2 (p.L263fs) in infants with closely similar severe interstitial lung disease (ILD), hypotonia, and congenital hypothyroidism. Functional analyses using A549 and HeLa cells revealed that NKX2-1-p.L263fs induced neither SFTPB nor SFTPC promoter activation and had a dominant negative effect on wild-type (WT) NKX2-1. In contrast,NKX2-1-p.R165W activated SFTPC, to a significantly greater extent than did WTNKX2-1, while SFTPB activation was only significantly reduced in HeLa cells. In accordance with our in vitro data, we found decreased amounts of SP-B and SP-C by western blot in bronchoalveolar lavage fluid (patient with p.L263fs) and features of altered surfactant protein metabolism on lung histology (patient with NKX2-1-p.R165W). In conclusion, ILD in patients with NKX2-1 mutations was associated with altered surfactant protein metabolism, and both gain and loss of function of the mutated NKX2-1 genes on surfactant protein promoters were associated with ILD in "Brain-Lung-Thyroid syndrome".
authors.affiliation: INSERM UMR 938, UPMC, Université Paris 6, France.
authors.forename: Loïc
authors.initials: L
authors.lastname: Guillot
authors.forename: Aurore
authors.initials: A
authors.lastname: Carré
authors.forename: Gabor
authors.initials: G
authors.lastname: Szinnai
authors.forename: Mireille
authors.initials: M
authors.lastname: Castanet
authors.forename: Elodie
authors.initials: E
authors.lastname: Tron
authors.forename: Francis
authors.initials: F
authors.lastname: Jaubert
authors.forename: Isabelle
authors.initials: I
authors.lastname: Broutin
authors.forename: François
authors.initials: F
authors.lastname: Counil
authors.forename: Delphine
authors.initials: D
authors.lastname: Feldmann
authors.forename: Annick
authors.initials: A
authors.lastname: Clement
authors.forename: Michel
authors.initials: M
authors.lastname: Polak
authors.forename: Ralph
authors.initials: R
authors.lastname: Epaud
mesh_terms: D000015:Abnormalities, Multiple / Q000000981:diagnostic imaging / Q000235:genetics* / Q000473:pathology; D000595:Amino Acid Sequence; D001483:Base Sequence; D001992:Bronchoalveolar Lavage Fluid; D045744:Cell Line, Tumor; D002648:Child; D002675:Child, Preschool; D004247:DNA; D017809:Fatal Outcome; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D017563:Lung Diseases, Interstitial / Q000150:complications / Q000000981:diagnostic imaging / Q000235:genetics* / Q000473:pathology; D008969:Molecular Sequence Data; D050505:Mutant Proteins / Q000737:chemistry / Q000378:metabolism; D009154:Mutation / Q000235:genetics*; D009687:Nuclear Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D009928:Organ Specificity / Q000235:genetics; D011247:Pregnancy; D011401:Promoter Regions, Genetic / Q000235:genetics*; D011485:Protein Binding; D037661:Pulmonary Surfactant-Associated Proteins / Q000235:genetics*; D011859:Radiography; D013577:Syndrome; D013961:Thyroid Gland / Q000473:pathology; D000074482:Thyroid Nuclear Factor 1; D014157:Transcription Factors / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism
chemical_list: D050505:Mutant Proteins; D009687:Nuclear Proteins; D037661:Pulmonary Surfactant-Associated Proteins; D000074482:Thyroid Nuclear Factor 1; D014157:Transcription Factors; D004247:DNA