Association of rare non-coding SNVs in the lung-specific FOXF1 enhancer with a mitigation of the lethal ACDMPV phenotype
Autor: | Xiaofei Song, Romana Gerychová, Jacques L. Michaud, Justyna A. Karolak, Qian Liu, Denis Bérubé, Brigitte H. W. Faas, Przemyslaw Szafranski, Nicole de Leeuw, Kathleen Gibbs, Petr Janku, Marta Jezova, Edwina J. Popek, Luc L. Oligny, Lea F. Surrey, Iveta Valášková, Virginie Poisson, Pawel Stankiewicz |
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Rok vydání: | 2019 |
Předmět: |
Alveolar capillary dysplasia
Adult Population Mutation Missense Biology Persistent Fetal Circulation Syndrome Polymorphism Single Nucleotide Article 03 medical and health sciences Genomic Imprinting Genetics medicine Missense mutation Humans Allele Enhancer education Child Genetics (clinical) 030304 developmental biology Sequence Deletion 0303 health sciences education.field_of_study Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7] 030305 genetics & heredity Other Research Radboud Institute for Health Sciences [Radboudumc 0] Infant Newborn Forkhead Transcription Factors medicine.disease Prognosis Phenotype Enhancer Elements Genetic Female Genomic imprinting Haploinsufficiency |
Zdroj: | Human Genetics, 138, 1301-1311 Hum Genet Human Genetics, 138, 11-12, pp. 1301-1311 |
ISSN: | 0340-6717 |
Popis: | Item does not contain fulltext Haploinsufficiency of FOXF1 causes alveolar capillary dysplasia with misalignment of pulmonary veins (ACDMPV), a lethal neonatal lung developmental disorder. We describe two similar heterozygous CNV deletions involving the FOXF1 enhancer and re-analyze FOXF1 missense mutation, all associated with an unexpectedly mitigated disease phenotype. In one case, the deletion of the maternal allele of the FOXF1 enhancer caused pulmonary hypertension and histopathologically diagnosed MPV without the typical ACD features. In the second case, the deletion of the paternal enhancer resulted in ACDMPV rather than the expected neonatal lethality. In both cases, FOXF1 expression in lung tissue was higher than usually seen or expected in patients with similar deletions, suggesting an increased activity of the remaining allele of the enhancer. Sequencing of these alleles revealed two rare SNVs, rs150502618-A and rs79301423-T, mapping to the partially overlapping binding sites for TFAP2s and CTCF in the core region of the enhancer. Moreover, in a family with three histopathologically-diagnosed ACDMPV siblings whose missense FOXF1 mutation was inherited from the healthy non-mosaic carrier mother, we have identified a rare SNV rs28571077-A within 2-kb of the above-mentioned non-coding SNVs in the FOXF1 enhancer in the mother, that was absent in the affected newborns and 13 unrelated ACDMPV patients with CNV deletions of this genomic region. Based on the low population frequencies of these three variants, their absence in ACDMPV patients, the results of reporter assay, RNAi and EMSA experiments, and in silico predictions, we propose that the described SNVs might have acted on FOXF1 enhancer as hypermorphs. |
Databáze: | OpenAIRE |
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