Association of rare non-coding SNVs in the lung-specific FOXF1 enhancer with a mitigation of the lethal ACDMPV phenotype

SZAFRANSKI, Przemyslaw, Qian LIU, Justyna A. KAROLAK, Xiaofei SONG, Nicole DE LEEUW, Brigitte FAAS, Romana GERYCHOVÁ, Petr JANKŮ, Marta JEŽOVÁ, Iveta VALÁŠKOVÁ, Kathleen A. GIBBS, Lea F. SURREY, Virginie POISSON, Denis BERUBE, Luc L. OLIGNY, Jacques L. MICHAUD, Edwina POPEK a Pawel STANKIEWICZ. Association of rare non-coding SNVs in the lung-specific FOXF1 enhancer with a mitigation of the lethal ACDMPV phenotype. Human Genetics. NEW YORK: SPRINGER, 2019, roč. 138, 11-12, s. 1301-1311. ISSN 0340-6717. Dostupné z: https://dx.doi.org/10.1007/s00439-019-02073-x.

Základní údaje

• Originální název: Association of rare non-coding SNVs in the lung-specific FOXF1 enhancer with a mitigation of the lethal ACDMPV phenotype
• Autoři: SZAFRANSKI, Przemyslaw (840 Spojené státy, garant), Qian LIU (840 Spojené státy), Justyna A. KAROLAK (840 Spojené státy), Xiaofei SONG (840 Spojené státy), Nicole DE LEEUW (528 Nizozemské království), Brigitte FAAS (528 Nizozemské království), Romana GERYCHOVÁ (203 Česká republika, domácí), Petr JANKŮ (203 Česká republika, domácí), Marta JEŽOVÁ (203 Česká republika, domácí), Iveta VALÁŠKOVÁ (203 Česká republika, domácí), Kathleen A. GIBBS (840 Spojené státy), Lea F. SURREY (840 Spojené státy), Virginie POISSON (124 Kanada), Denis BERUBE (124 Kanada), Luc L. OLIGNY (124 Kanada), Jacques L. MICHAUD (124 Kanada), Edwina POPEK (840 Spojené státy) a Pawel STANKIEWICZ (840 Spojené státy).
• Vydání: Human Genetics, NEW YORK, SPRINGER, 2019, 0340-6717.

Další údaje

• Originální jazyk: angličtina
• Typ výsledku: Článek v odborném periodiku
• Obor: 10603 Genetics and heredity
• Stát vydavatele: Spojené státy
• Utajení: není předmětem státního či obchodního tajemství
• WWW: URL
• Impakt faktor: Impact factor: 5.743
• Kód RIV: RIV/00216224:14110/19:00112517
• Organizační jednotka: Lékařská fakulta
• Doi: http://dx.doi.org/10.1007/s00439-019-02073-x
• UT WoS: 000493929500001
• Klíčová slova anglicky: ALVEOLAR-CAPILLARY DYSPLASIA; MICE HETEROZYGOUS NULL; PULMONARY VEINS; GENE FOXF1; MISALIGNMENT; TRANSCRIPTION; VARIANTS; VESSELS; HAPLOINSUFFICIENCY; EXPRESSION
• Štítky: 14110212, 14110230, 14110411, 14110611, rivok
• Příznaky: Mezinárodní význam, Recenzováno

Anotace

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.