Bzdęga Katarzyna, Deutsch Gail H, Rydzanicz Małgorzata, Błaż Witold, Rafińska-Ważny Elżbieta, Terpin Anna P, Klepach Dariia, Zakharova Valentyna, Płoski Rafał, Szczapa Tomasz, Karolak Justyna A
Chair and Department of Genetics and Pharmaceutical Microbiology, Poznan University of Medical Sciences, Poznan, Poland.
Doctoral School, Poznan University of Medical Sciences, Poznan, Poland.
Am J Med Genet A. 2025 Aug;197(8):e64071. doi: 10.1002/ajmg.a.64071. Epub 2025 Mar 27.
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.
致死性肺发育障碍（LLDDs）在组织学上分为肺静脉错位的肺泡毛细血管发育异常（ACDMPV）、先天性肺泡发育异常（CAD）、腺泡发育异常（AcDys）和原发性肺发育不全（PH），是与难治性呼吸衰竭导致的高新生儿死亡率相关的罕见疾病。虽然ACDMPV大多由涉及FOXF1的单核苷酸变异（SNV）或拷贝数变异（CNV）引起，但AcDys、CAD和PH常与TBX4或FGF10内的异常有关。这些基因在SHH-FOXF1和TBX4-FGF10信号网络中相互作用，是已知的肺发育调节因子。最近在TBX4、FGF10或FOXF1缺陷的LLDD肺中进行的研究显示，在转录组和免疫组化水平上TMEM100的表达降低。在此，我们报告了4例经基因和组织病理学确诊的LLDD新患者，包括ACDMPV（n = 2）、AcDys（n = 1）和PH（n = 1），我们在其中检测到涉及FOXF1（n = 2）或TBX4（n = 2）的杂合变异。在这些新生儿的肺组织中进行的额外免疫组化（TMEM100）和qPCR分析（TMEM100、TBX4、FOXF1）显示，TMEM100、TBX4和FOXF1的表达显著降低。我们的结果证实了先前的发现，表明TMEM100可能参与FOXF1-TBX4-FGF10分子信号传导，当该信号传导被破坏时，可能导致LLDD。
