Two deletions overlapping a distant FOXF1 enhancer unravel the role of lncRNA LINC01081 in etiology of alveolar capillary dysplasia with misalignment of pulmonary veins. Issue 8 (19th May 2014)

• Record Type: Journal Article
• Authors: Szafranski, Przemyslaw; Dharmadhikari, Avinash V.; Wambach, Jennifer A.; Towe, Chris T.; White, Frances V.; Grady, R. Mark; Eghtesady, Pirooz; Cole, F. Sessions; Deutsch, Gail; Sen, Partha; Stankiewicz, Paweł
• Is Part Of: American journal of medical genetics. Volume 164:Issue 8(2014.)
• Page Start: 2013
• Page End: 2019
• Publication Date: 2014-05-19
• Subjects: Medical genetics -- Periodicals; 616.14205
• DOI: 10.1002/ajmg.a.36606
• Languages: English
• ISSNs: 1552-4825

Abstract

<abstract abstract-type="main"> <title> <x xml:space="preserve">Abstract</x> </title> <sec id="ajmga36606-sec-0001" sec-type="section"> <p>Position effects due to disruption of distant <italic>cis</italic>‐regulatory regions have been reported for over 40 human gene loci; however, the underlying mechanisms of long‐range gene regulation remain largely unknown. We report on two patients with alveolar capillary dysplasia with misalignment of pulmonary veins (ACDMPV) caused by overlapping genomic deletions that included a distant <italic>FOXF1</italic> transcriptional enhancer mapping 0.3 Mb upstream to <italic>FOXF1</italic> on 16q24.1. In one patient with atypical late‐onset ACDMPV, a ∼1.5 Mb deletion removed the proximal 43% of this enhancer, leaving the lung‐specific long non‐coding RNA (lncRNA) gene <italic>LINC01081</italic> intact. In the second patient with severe neonatal‐onset ACDMPV, an overlapping ∼194 kb deletion disrupted <italic>LINC01081</italic>. Both deletions arose de novo on maternal copy of the chromosome 16, supporting the notion that <italic>FOXF1</italic> is paternally imprinted in the human lungs. RNAi‐mediated knock‐down of <italic>LINC01081</italic> in normal fetal lung fibroblasts showed that this lncRNA positively regulates <italic>FOXF1</italic> transcript level, further indicating that decrease in <italic>LINC01081</italic> expression can contribute to development of ACDMPV. © 2014 Wiley Periodicals, Inc.</p> </sec> </abstract>