Decreased Level of TMEM100 in Neonates With Lethal Lung Developmental Disorders due to Abnormalities in SHH-FOXF1 and...

Lethal lung developmental disorders (LLDDs), histologically classified as alveolar capillary dysplasia with misalignment of pulmonary veins (ACDMPV), congenital alveolar dysplasia (CAD), acinar dysplasia (AcDys), and primary pulmonary hypoplasia (PH), are rare diseases associated with high neonatal mortality due to refractory respiratory failure. Although ACDMPV mostly results from single nucleotide variants (SNVs) or copy-number variants (CNVs) involving FOXF1, AcDys, CAD, and PH are often associated with abnormalities within TBX4 or FGF10. These genes interact in the SHH-FOXF1 and TBX4-FGF10 signaling network and are known regulators of lung development. Recent studies conducted in TBX4-, FGF10-, or FOXF1-deficient LLDD lungs revealed decreased expression of TMEM100 at the transcriptomic and immunohistochemical levels. Here, we present four new patients with genetically and histopathologically confirmed LLDD, including ACDMPV (n = 2), AcDys (n = 1), and PH (n = 1), in whom we detected a heterozygous variants involving FOXF1 (n = 2) or TBX4 (n = 2). Additional immunohistochemical (TMEM100) and qPCR analyses (TMEM100, TBX4, FOXF1) performed in lung tissues of these newborns revealed a significant reduction in TMEM100, TBX4, and FOXF1 expression. Our results confirm previous findings indicating the possible involvement of TMEM100 in FOXF1-TBX4-FGF10 molecular signaling that, when disrupted, may lead to LLDD.