A de novo 2.2 Mb recurrent 17q23.1q23.2 deletion unmasks novel putative regulatory non-coding SNVs associated with lethal lung hypoplasia and pulmonary hypertension: a case report

Karolak, Justyna A.; Gambin, Tomasz; Honey, Engela; Slavík, Tomáš; Popek, Edwina J.; Stankiewicz, Paweł

doi:10.1186/s12920-020-0701-6

Cited by 15 publications

(18 citation statements)

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“…The increase of SHH pathway expression in ACDMPV could represent a compensatory response to the loss of FOXF1. In addition to FOXF1, SHH is thought to control expression of the TBX genes, which are also associated with LLDD and PAH in humans [64][65][66][67][68][69] and are known regulators of lung branching in mice [70,71]. Of note, in our recent ChIP-seq study performed in IMR-90 fetal lung fibroblasts, we demonstrated that TBX2 and/ or TBX4 bind to FOXF1, FENDRR, their promoter(s) and lung-specific enhancer, as well as to genes from the axon guidance/SEMA signaling (SEMAs, PLXNs, and NRP), that were found to be deregulated in ACDMPV patients in this study.…”

Section: Discussionmentioning

confidence: 99%

Perturbation of semaphorin and VEGF signaling in ACDMPV lungs due to FOXF1 deficiency

et al. 2021

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Background Alveolar capillary dysplasia with misalignment of pulmonary veins (ACDMPV) is a rare lethal congenital lung disorder in neonates characterized by severe progressive respiratory failure and refractory pulmonary hypertension, resulting from underdevelopment of the peripheral pulmonary tree. Causative heterozygous single nucleotide variants (SNVs) or copy-number variant (CNV) deletions involving FOXF1 or its distant lung-specific enhancer on chromosome 16q24.1 have been identified in 80–90% of ACDMPV patients. FOXF1 maps closely to and regulates the oppositely oriented FENDRR, with which it also shares regulatory elements. Methods To better understand the transcriptional networks downstream of FOXF1 that are relevant for lung organogenesis, using RNA-seq, we have examined lung transcriptomes in 12 histopathologically verified ACDMPV patients with or without pathogenic variants in the FOXF1 locus and analyzed gene expression profile in FENDRR-depleted fetal lung fibroblasts, IMR-90. Results RNA-seq analyses in ACDMPV neonates revealed changes in the expression of several genes, including semaphorins (SEMAs), neuropilin 1 (NRP1), and plexins (PLXNs), essential for both epithelial branching and vascular patterning. In addition, we have found deregulation of the vascular endothelial growth factor (VEGF) signaling that also controls pulmonary vasculogenesis and a lung-specific endothelial gene TMEM100 known to be essential in vascular morphogenesis. Interestingly, we have observed a substantial difference in gene expression profiles between the ACDMPV samples with different types of FOXF1 defect. Moreover, partial overlap between transcriptome profiles of ACDMPV lungs with FOXF1 SNVs and FENDRR-depleted IMR-90 cells suggests contribution of FENDRR to ACDMPV etiology. Conclusions Our transcriptomic data imply potential crosstalk between several lung developmental pathways, including interactions between FOXF1-SHH and SEMA-NRP or VEGF/VEGFR2 signaling, and provide further insight into complexity of lung organogenesis in humans.

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Section: Discussionmentioning

confidence: 99%

Perturbation of semaphorin and VEGF signaling in ACDMPV lungs due to FOXF1 deficiency

et al. 2021

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“…In the studies of Karolak J.A. et al, a complex inheritance of lethal developmental disorders of the lungs due to disruption of the TBX-FGF pathway has been described [ 86 ]. The emergence of rare coding variants involving FGF10 with putative hypomorphic noncoding SNVs implies a complex inheritance of pulmonary hypoplasias.…”

Section: Resultsmentioning

confidence: 99%

The “Angiogenic Switch” and Functional Resources in Cyclic Sports Athletes

Balberova

Быков

Shnayder

et al. 2021

IJMS

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Regular physical activity in cyclic sports can influence the so-called “angiogenic switch”, which is considered as an imbalance between proangiogenic and anti-angiogenic molecules. Disruption of the synthesis of angiogenic molecules can be caused by local changes in tissues under the influence of excessive physical exertion and its consequences, such as chronic oxidative stress and associated hypoxia, metabolic acidosis, sports injuries, etc. A review of publications on signaling pathways that activate and inhibit angiogenesis in skeletal muscles, myocardium, lung, and nervous tissue under the influence of intense physical activity in cyclic sports. Materials: We searched PubMed, SCOPUS, Web of Science, Google Scholar, Clinical keys, and e-LIBRARY databases for full-text articles published from 2000 to 2020, using keywords and their combinations. Results: An important aspect of adaptation to training loads in cyclic sports is an increase in the number of capillaries in muscle fibers, which improves the metabolism of skeletal muscles and myocardium, as well as nervous and lung tissue. Recent studies have shown that myocardial endothelial cells not only respond to hemodynamic forces and paracrine signals from neighboring cells, but also take an active part in heart remodeling processes, stimulating the growth and contractility of cardiomyocytes or the production of extracellular matrix proteins in myofibroblasts. As myocardial vascularization plays a central role in the transition from adaptive heart hypertrophy to heart failure, further study of the signaling mechanisms involved in the regulation of angiogenesis in the myocardium is important in sports practice. The study of the “angiogenic switch” problem in the cerebrovascular and cardiovascular systems allows us to claim that the formation of new vessels is mediated by a complex interaction of all growth factors. Although the lungs are one of the limiting systems of the body in cyclic sports, their response to high-intensity loads and other environmental stresses is often overlooked. Airway epithelial cells are the predominant source of several growth factors throughout lung organogenesis and appear to be critical for normal alveolarization, rapid alveolar proliferation, and normal vascular development. There are many controversial questions about the role of growth factors in the physiology and pathology of the lungs. The presented review has demonstrated that when doing sports, it is necessary to give a careful consideration to the possible positive and negative effects of growth factors on muscles, myocardium, lung tissue, and brain. Primarily, the “angiogenic switch” is important in aerobic sports (long distance running). Conclusions: Angiogenesis is a physiological process of the formation of new blood capillaries, which play an important role in the functioning of skeletal muscles, myocardium, lung, and nervous tissue in athletes. Violation of the “angiogenic switch” as a balance between proangiogenic and anti-angiogenic molecules can lead to a decrease in the functional resources of the nervous, musculoskeletal, cardiovascular, and respiratory systems in athletes and, as a consequence, to a decrease in sports performance.

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“…Infants with LLDD who had a pathogenic TBX4 or FGF10 variant also had at least one noncoding rare SNV within the predicted lung-specific enhancer located upstream to TBX4. We hypothesized that those noncoding variants decreased the activity of the enhancer causing in trans reduction of TBX4 or FGF10 expression and resulting in LLDD (Karolak et al, 2020(Karolak et al, , 2019. Moreover, TBX4 pLI score of 0.5 indicates that a deleterious variant alone might not be sufficient to cause a disease and the variability in the phenotype can be explained by the contribution of the other variants in the regulatory elements (Table S1).…”

Section: Discussionmentioning

confidence: 99%

Exacerbation of mild lung disorders to lethal pulmonary hypoplasia by a noncoding hypomorphic SNV in a lung‐specific enhancer in trans to the frameshifting TBX4 variant

Bölükbaşı

Karolak

Szafrański

et al. 2022

American J of Med Genetics Pt A

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Variants involving TBX4 are associated with a wide variety of disorders, including pulmonary arterial hypertension, ischiocoxopodopatellar syndrome (ICPPS)/small patella syndrome (SPS), lethal lung developmental disorders (LLDDs) in neonates, heart defects, and prenatally lethal posterior amelia with pelvic and pulmonary hypoplasia syndrome. The objective of our study was to elucidate the wide variable phenotypic expressivity and incomplete penetrance in a three‐generation family with a truncating variant in TBX4. In addition to exome and genome sequencing analyses, a candidate noncoding regulatory single nucleotide variant (SNV) within the lung‐specific TBX4 enhancer was functionally tested using an in vitro luciferase reporter assay. A heterozygous frameshift variant c.1112dup (p.Pro372Serfs*14) in TBX4 was identified in patients with mild interstitial lung disease (1), bronchiolitis obliterans (1), recurrent pneumothorax (1), ICPPS/SPS (1), LLDD (2), and in unaffected individuals (4). In two deceased neonates with LLDD, we identified a noncoding SNV rs62069651‐C located in trans to the mutated TBX4 allele that reduced the TBX4 promoter activity by 63% in the reporter assay. Our findings provide a functional evidence for the recently reported model of complex compound inheritance in which both TBX4 coding and in trans noncoding hypomorphic variants in the lung‐specific enhancer of TBX4 contribute to LLDD.

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A de novo 2.2 Mb recurrent 17q23.1q23.2 deletion unmasks novel putative regulatory non-coding SNVs associated with lethal lung hypoplasia and pulmonary hypertension: a case report

Cited by 15 publications

References 59 publications

Perturbation of semaphorin and VEGF signaling in ACDMPV lungs due to FOXF1 deficiency

Perturbation of semaphorin and VEGF signaling in ACDMPV lungs due to FOXF1 deficiency

The “Angiogenic Switch” and Functional Resources in Cyclic Sports Athletes

Exacerbation of mild lung disorders to lethal pulmonary hypoplasia by a noncoding hypomorphic SNV in a lung‐specific enhancer in trans to the frameshifting TBX4 variant

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