Two deletions overlapping a distant FOXF1 enhancer unravel the role of lncRNA LINC01081 in etiology of alveolar capillary dysplasia with misalignment of pulmonary veins

Position effects due to disruption of distant cis‐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 vei...

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Published in:American journal of medical genetics. Part A 2014-08, Vol.164A (8), p.2013-2019
Main 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
Format: Article
Language:English
Subjects:
ACDMPV
Adult
Biopsy
Comparative Genomic Hybridization
DNA Mutational Analysis
Enhancer Elements, Genetic
Female
Forkhead Transcription Factors - genetics
Gene Expression
gene regulation
genomic imprinting
Humans
Infant, Newborn
long non-coding RNA
Lung - diagnostic imaging
Lung - pathology
Male
Persistent Fetal Circulation Syndrome - genetics
position effect
Radiography
RNA Interference
RNA, Long Noncoding - genetics
RNA, Messenger - genetics
Sequence Deletion
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Summary:Position effects due to disruption of distant cis‐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 FOXF1 transcriptional enhancer mapping 0.3 Mb upstream to FOXF1 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 LINC01081 intact. In the second patient with severe neonatal‐onset ACDMPV, an overlapping ∼194 kb deletion disrupted LINC01081. Both deletions arose de novo on maternal copy of the chromosome 16, supporting the notion that FOXF1 is paternally imprinted in the human lungs. RNAi‐mediated knock‐down of LINC01081 in normal fetal lung fibroblasts showed that this lncRNA positively regulates FOXF1 transcript level, further indicating that decrease in LINC01081 expression can contribute to development of ACDMPV. © 2014 Wiley Periodicals, Inc.
ISSN:1552-4825
1552-4833
DOI:10.1002/ajmg.a.36606