TY - JOUR
T1 - Two deletions overlapping a distant FOXF1 enhancer unravel the role of lncRNA LINC01081 in etiology of alveolar capillary dysplasia with misalignment of pulmonary veins
AU - Szafranski, Przemyslaw
AU - Dharmadhikari, Avinash V.
AU - Wambach, Jennifer A.
AU - Towe, Chris T.
AU - White, Frances V.
AU - Grady, R. Mark
AU - Eghtesady, Pirooz
AU - Cole, F. Sessions
AU - Deutsch, Gail
AU - Sen, Partha
AU - Stankiewicz, Paweł
PY - 2014/8
Y1 - 2014/8
N2 - 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 0.3Mb upstream to FOXF1 on 16q24.1. In one patient with atypical late-onset ACDMPV, a ~1.5Mb 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 ~194kb 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.
AB - 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 0.3Mb upstream to FOXF1 on 16q24.1. In one patient with atypical late-onset ACDMPV, a ~1.5Mb 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 ~194kb 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.
KW - ACDMPV
KW - Gene regulation
KW - Genomic imprinting
KW - Long non-coding RNA
KW - Position effect
UR - http://www.scopus.com/inward/record.url?scp=84904423684&partnerID=8YFLogxK
U2 - 10.1002/ajmg.a.36606
DO - 10.1002/ajmg.a.36606
M3 - Article
C2 - 24842713
AN - SCOPUS:84904423684
SN - 1552-4825
VL - 164
SP - 2013
EP - 2019
JO - American Journal of Medical Genetics, Part A
JF - American Journal of Medical Genetics, Part A
IS - 8
ER -