The S52F FOXF1 Mutation Inhibits STAT3 Signaling and Causes Alveolar Capillary Dysplasia

A recurrent 8 bp frameshifting indel in FOXF1 defines a novel mutation hotspot associated with alveolar capillary dysplasia with misalignment of pulmonary veins

“…NMDEscPredictor (Coban-Akdemir et al, 2018) showed that the c.691_698del variant is expected to be subject to degradation by nonsense-mediated decay and thus to lead to FOXF1 haploinsufficiency. Interestingly, we have reported the same variant in two unrelated ACDMPV patients 69.4 (pt#6) (Sen et al, 2013) and 187.3 (Pradhan et al, 2019).…”

“…Patient 187.3, reported by Pradhan et al, (2019), was born at 35 3/7 weeks with a birthweight of 2325 g and Apgar scores 3/1 and 7/5. Pregnancy was complicated by fetal hypoplastic left heart, polyhydramnios, and enlarged fetal stomach.…”

“…Alveolar capillary dysplasia with misalignment of pulmonary veins (ACDMPV, MIM# 265380) is a rare neonatal developmental lung disease, lethal due to severe respiratory distress and refractory pulmonary hypertension (PAH) (Bishop, Stankiewicz, & Steinhorn, 2011). To date, more than 70 distinct ACDMPV-related FOXF1 heterozygous point mutations and 60 copy-number variant (CNV) deletions involving FOXF1 and/or its upstream lung-specific enhancer at 16q24.1 have been identified in 80–90% of ACDMPV patients (Abu-El-Haija et al, 2018; Everett, Ataliotis, Chioza, Shaw-Smith, & Chung, 2017; Hayasaka et al, 2018; Ma et al, 2017; Nagano, Yoshikawa, Hosono, Takahashi, & Nakayama, 2016; Pradhan et al, 2019; Sen, Gerychova, et al, 2013; Stankiewicz et al, 2009; Szafranski et al, 2013, 2014, 2016). FOXF1 (Forkhead box F1, MIM#601089) encodes a transcription factor of the fork-head family, and is regulated by the sonic hedgehog (SHH) signaling pathway during lung development (Fernandes-Silva, Correia-Pinto, & Moura, 2017; Kalinichenko et al, 2001).…”

A Step toward Treating a Lethal Neonatal Lung Disease. STAT3 and Alveolar Capillary Dysplasia

“…In this issue of the Journal , Pradhan and colleagues (pp. 1045–1056) expand our knowledge of the molecular mechanisms by which FOXF1 mutations cause disease and offer a glimmer of hope for treatment for this universally fatal disorder (10). They selected for study a mutation identified in an infant with ACDMPV that resulted in the substitution of phenylalanine for S52F (serine in codon 52).…”

“…Although ACDMPV is a rare disease, with the recognition of the causative role of FOXF1 mutations and deletions, clinical genetic testing is now routinely available, allowing for noninvasive diagnosis. As a result, the number of identified cases has increased dramatically in recent years, as exemplified by the additional 28 cases included in the report (10). Could delivery of STAT3 complementary DNA using nanoparticles, which are being used in clinical trials for human malignancies, be used to treat human infants with ACDMPV?…”